certainly also holds true for the immune-related mechanisms
that are triggered by radiation exposure.
II. Dose-rate effects on
malignant cells
As noted above, evaluation of
dose-rate effects on the survival of tumor cells began more than 40 years ago.
Some of the early findings are described in detail in publications from the
1980s and 1990s (Kelland and Steel, 1986; Steel et al, 1987; Steel, 1991,
1996). Dose rate dependence has been noted for some, but not all, of the
malignant cell populations that have been tested. The reported variability and
sometimes contradictory results make generalizations difficult. Selected
relevant publications are summarized on the basis of tumor type in the following
sections.
A.
Brain tumor
In 2004, 18,400 new cases of brain and other nervous
system cancers and 12,690 deaths were estimated to have occurred in the United
States (Jemal et al, 2004). Although not among the most common neoplasms,
high-grade malignant tumors of the brain are among the most deadly and also
among the most radioresistant type of cancer. The radioresistance has been well
documented in reports of local recurrence within the targeted volume even after
relatively high radiation doses (Wallner et al, 1989). Proposed mechanisms that
may account for the resistance include radiation-induced up-regulation of
antioxidant enzymes within the tumor cells (Lee et al, 2004), overexpression of
epidermal growth factor receptors (EGFR) (Barker et al, 2001) and low
expression of bax, a pro-apoptotic protein (Shu et al, 1998; Streffer et al,
2002). In addition, the possibility of tumor escape from immune surveillance by
the production of transforming growth factor-b2 (TGF-b2), a highly immunosuppressive cytokine that is secreted by the
majority of glioblastomas, is under investigation (Kingsley-Kallesen et al,
2001; Strege et al, 2004). Although TGF-b2 was not tested for, the pattern of cytokine mRNA expression in five
human glioblastoma cell lines has been shown to be dependent upon radiation
dose rate (Ross et al, 1997). Dose rates of 0.0035 Gy/min and 0.01 Gy/min
generally reduced the mRNA levels for IL-1b and IL-6 compared to unirradiated control cells. On the other hand,
exposures at 0.041 Gy/min and 2 Gy/min increased mRNA for both cytokines. This
study also showed that the 0.041 Gy/min intermediate dose rate was less toxic
than the lower and higher dose rates. Although cytokine gene expression did not
have a clear effect on glioblastoma cell survival in this in vitro study, the
investigators speculated that tumor-derived cytokines may be important to
radiation response in vivo by affecting immune cells, tumor stroma,
vasculature, or surrounding tissues.
The response of five human glioblastoma cells lines
(T98G, A7, U87MG, U138 and HGL21) and one grade III astrocytoma cell line
(U373) to low-dose radiation was investigated in culture (Short et al, 1999).
All of these cell lines had been previously shown to be relatively
radioresistant. Clonogenic survival was the measured end point after single
doses of X-rays (0.05 to 5 Gy) were applied to the cells at 0.2 - 0.4 Gy/min. Low-dose hypersensitivity (i.e. less clonogenic survival than
is predicted by a linear-quadratic fit to higher doses) was observed in five of the six cell lines below a
total dose of 1 Gy, with the most dramatic effect occurring with the A7, U138
and T98G cells; no hypersensitivity was noted for the U373 astrocytoma cells.
Lack of an inverse dose-rate effect on U373 cell survival has also been
reported in other studies (Mitchell et al, 2002). Overall, this work supports
the premise that low-dose hypersensitivity is a common, although not universal,
feature of radioresistant human glioma cell lines. It also suggests that repair
mechanisms induced by high, but not low, radiation doses may be an important
component of tumor radioresistance. Large, acute doses may generate damage
above a certain threshold that is needed to activate repair processes that are
more efficient than those that function in constitutive DNA maintenance.
However, recent studies by Marples and colleagues, in which a flow
cytometry-based clonogenic survival assay was utilized to assess responses of
hamster V79 and human T98G and U373 cells, have demonstrated that low-dose hyper-radiosensitivity
exists for asynchronous and G2-phase enriched cell populations (Marples et al,
2003). These findings indicate that the underlying mechanism for increased
radiosensitivity at low doses may be a consequence of radiation-damaged G2-phase
cells entering mitosis prematurely, rather than induction of DNA repair.
These and similar data suggest the possibility
that delivering a series of small doses per day (ÔultrafractionationÕ) could
result in increased destruction of radioresistant tumors compared to the same
total dose given in conventional 2 Gy fractions (Marin et al, 1991; Short et
al, 2001). Results for most human
tumor cell lines indicate that increased sensitivity per unit dose occurs when
radiation is delivered acutely within the range of 0.05 Gy to 0.5 Gy/fraction
(Joiner et al, 2001).
In a follow-up publication, the effect of
ultrafractionated radiation on A7 glioma growing subcutaneously (s.c.) in
athymic nude mice was determined (Krause et al, 2003). The A7 cells were among
those that had previously shown a striking increase in radiosensitivity with
ultrafractionated irradiation in vitro.
Tumors were irradiated either with 126 fractions at 0.4 Gy/fraction or with 30
fractions at 1.68 Gy/fraction over a period of 6 weeks. A total dose of 50.4 Gy
was delivered to both groups of animals. No increase in radiosensitivity was
evident with ultrafractionation. In fact, a significant decrease in tumor growth delay occurred with ultrafractionation
compared to the more conventional 1.68 Gy/fraction. The investigators noted
that simplistic extrapolation from data obtained in vitro is not sufficient to predict the outcome in vivo and that comprehensive
evaluation of new treatment options in animal models is essential before
contemplating translation to the clinic.
Other investigators have also noted lack of
correlation between human glioma cell lines when exposed to fractionated
radiation schemes in vitro and when
treated as xenografted tumors in athymic rodents (Baumann et al, 1992), as well
as increasing glioma cell survival as the radiation dose rate is reduced (Yang
et al, 1990). In one of these studies, Yang and colleagues evaluated 16 clones
of an early-passage human glioma cell line (IN859) based on DNA content, modal
chromosome number, morphology and radiosensitivity (Yang et al, 1992). The
radiation dose that gave a survival fraction of 0.01 varied by a factor of
~1.5. Comparison of the most sensitive and most resistant clones at a fixed
total dose surprisingly demonstrated that the sensitive clone exhibited greater
survival after split-dose irradiation. Finally, with T98G glioblastoma cells, a
sparing effect was noted when the dose rate was reduced from 60 cGy/hr to 30
cGy/hr (Mitchell et al, 2002).
The above findings, although somewhat disappointing,
certainly do not disprove the existence of low-dose hyper-radiosensitivity for
tumors originating in the CNS. In a very recent study by Chalmers and
colleagues, the effects of four different poly(ADP-ribose) polymerase-1
(PARP-1) inhibitors on low-dose (0.5 – 0.3 Gy) radiosensitivity were
evaluated using T98G and U373-MG human glioma cell lines (Chalmers et al,
2004). Hamster fibroblasts (V79-379A and CHO-K1) and mouse embryo fibroblasts
(3T3) were also included in this study. Inhibition of PARP-1 resulted in
sensitization of the glioma and most of the other cell lines to the low-dose
radiation; the only exception was the mouse 3T3 fibroblast line (i.e. PARP-1
knockout cells). The investigators suggested that PARP-1 inhibitors may be
therapeutically valuable in radiotherapy regimens that consist of multiple
small doses or continuous LDR radiation because of the enhanced inhibition of
PARP-1 on rapidly dividing tumor cells. PARP-1 is an enzyme that binds rapidly
to single- and double-stand DNA breaks and modulates the activity of many
nuclear proteins (DÕAmours et al, 1999; Herceg and Wang, 2001). Deficiency in
PARP-1 results in severely impaired base excision repair and genomic
instability in response to low-dose radiation (Shall and de Murcia, 2000).
An encouraging in
vivo study by Williams and colleagues combined ULDR radiation together with
HDR radiation using athymic mice that were s.c. implanted with U251 human
malignant glioma cells (Williams et al, 1998). The ULDR radiation was delivered
locally as intratumorally implanted 125I seeds (0.05 Gy/hr) or from
an external 137Cs source (0.037 Gy/hr) that provided whole-body
exposure. The external beam HDR radiation treatments were initiated 3 days
later and consisted of 2 Gy x 8 daily fractions and 5 Gy x 2 daily fractions.
These time-dose regimens were selected because they are clinically feasible and
because previous experiments predicted equal growth delay of the tumor. The
ULDR radiation alone had little or no effect on tumor progression and the two
HDR external beam schedules resulted in a 20-25 day growth delay. However, the
continuous administration of ULDR radiation with either 125I seeds
or whole-body exposure to 137Cs significantly increased efficacy of
the HDR treatments. A delay of 33-35 days in growth of the glioma was obtained
with the combination treatments.
125I seed
implants together with fractionated HDR external beam radiation have been
explored in treating patients with malignant brain tumors. In one study, a
comparison was made between temporary 125I implants with a dose rate
of 0.4 Gy/hr (total dose was 60 Gy) and permanent 125I seeds with a
dose rate of 0.04 - 0.07 Gy/hr (total dose was 100-120 Gy); the two protracted
regimens were delivered concurrently with external beam radiotherapy to a total
of 50 Gy (Zamorano et al, 1992). The investigators concluded that use of either
of these implants together with external radiation seemed to offer the best
chance for long-term survival without deterioration of the clinical condition.
In another report, 48 patients (after brain tumor resection) received permanent
low-activity 125I implants together with conventional external beam
therapy; 38 of these subjects were implanted 1-2 weeks before external beam
treatment was initiated and 10 received external radiation before the implant
(Fernandez et al, 1995). At the time of publication, median survival was
greater than 31 months for patients with anaplastic astrocytoma and greater
than 23 months in cases of glioblastoma. These are promising results, since
median survival after sequential conventional radiotherapy and HDR temporary 125I
implantation is only ~22 months (Scharfen et al, 1992).
B.
Prostate tumor
Adenocarcinoma of the prostate is the leading cancer
diagnosed and the second most common cause of cancer-related mortality in males
residing in the United States. According to estimates of the American Cancer
Society, there were approximately 230,110 newly diagnosed cases of prostate
cancer and 29,900 deaths due to the disease in 2004 (Jemal et al, 2004). Most
patients presenting with prostate cancer have localized disease and are
candidates for radiation therapy. Exposure to fractionated HDR radiation is a
standard treatment for localized prostate cancer. With conventional radiation
time-dose regimens, historical local recurrence rates range from 25% to 62%,
leaving considerable room for improvement. Protocols that increase local
control are likely to be very important in mitigating the subsequent
development of distant metastases and prolonging survival (Fuks et al, 1991;
Kaplan et al, 1994). The still relatively high incidence of side effects (e.g.
proctitis, rectal bleeding, increased urinary frequency, urethral stricture and
gastrointestinal complications) is also a major concern.
Studies describing tumor cell responses to LDR/HDR
radiation combinations present the possibility that radiotherapy of prostate
cancer could be substantially improved. Most prostate cancer cell lines require
relatively large doses of HDR radiation to produce significant cell death
(Wollin et al, 1989; Smalley et al, 1991; Kaver et al, 1991; Leith et al, 1993;
Leith, 1994). Prostate cancer cells subjected to a single acute dose of 2 Gy (a
commonly used dose/fraction in prostate cancer radiotherapy) generally have a survival
fraction of approximately 0.56 (DeWeese et al, 1998), whereas the survival
fraction of the more radiosensitive lymphomas is often <0.35 under similar
conditions (Jones et al, 1973; Malaise et al, 1986).
A study by DeWeese and colleagues showed that the
LNCaP prostate cancer cell line with wild type p53 is relatively sensitive to
killing by LDR radiation (0.25 Gy/hr), but that protracted exposure does not
result in increased killing compared to fractionated HDR exposure (1 Gy/min)
(DeWeese et al, 1998). On the other hand, PC-3 cells, a human prostate cancer
cell line with mutant p53, were relatively resistant to LDR radiation, but a
higher fraction were killed with protracted LDR exposure than with fractionated
radiation delivered at a high-dose rate. It was also found, using flow
cytometry analysis, that LDR irradiation of LNCaP cells resulted in their
accumulation at both G1/S and G2/M cell cycle transition points, whereas PC-3
cells were arrested only at G2/M. The investigators concluded that, rather
unexpectedly, the radiation-induced cell cycle distribution pattern (G1/S and
G2/M versus G2/M alone) seemed to have little effect on survival after
irradiation at low-dose rates. TP53
gene status also appeared to play no significant role. In another study, these
same investigators found that two related sublines exhibited different cell
cycle phase distributions, but similar degrees of increased radiosensitivity
after LDR irradiation (DeWeese et al, 1997). Our pilot experiments comparing
the efficacy of photons (60Co g-rays) and protons have demonstrated that human LNCaP prostate
carcinoma cells have a significantly lower surviving cell fraction when
irradiated with proton radiation (modulated Bragg peak of 250 MeV) than photon
radiation at the same physical dose between the range of 2 – 4 Gy (p =
0.02); by 16 hours DNA synthesis was lower for LNCaP cells irradiated with
protons compared to photons (p = 0.01) (Baer et al, 2000). Based on several characteristics, the LNCaP cells resemble
prostate tumor cells in patients with localized disease more closely than most
other human prostate tumor cell lines in that they: a) are hormone responsive
(Newmark et al, 1992); b) possess wild-type TP53
and the level of p53 protein increases upon exposure to DNA-damaging agents
(Nelson et al, 1996; Newmark et al, 1992); and c) produce prostate acid
phosphatase (PAP) and prostate-specific antigen (PSA) (Gau et al, 1997; Young
et al, 1991). Collectively, these observations together
with the greater accuracy of proton beams in tumor targeting, support dose
escalation with protons in combination with LDR protocols.
In a clinical trial at the Mayo Clinic and William
Beaumont Hospital, 57 patients with newly diagnosed bulky prostatic carcinoma
(9% with stage B2 and 91% with stage C) were treated preoperatively with 5 Gy
in one fraction, underwent pelvic lymphadenectomy and received 30-35 Gy from
interstitially implantated iridium-192 (192Ir) seeds and received
30.6 Gy external beam irradiation in 17 fractions (Stromberg et al, 1994). The
radiation from the 192Ir seeds had an LDR of 0.7-0.8 Gy/hour and was
delivered over a period of approximately 3 weeks between the two external beam
treatments. The 5-year actuarial survival rate of 85% compared favorably with
5-year survival rates of 58-62% for stage C prostate cancer reported with
external beam radiotherapy alone (Hanks et al, 1987; Bagshaw et al, 1990). The
5-year disease-free survival of 63% was similar to that observed after only
external beam therapy (Arcangeli et al, 1991; Perez et al, 1988), indicating
that distant spread is an important factor in the final outcome. The
investigators suggested that the relatively high 5-year actuarial local control
rates of 94% and 79.5% (clinical and pathological, respectively) may reflect a higher
radiobiologically effective dose delivered to the prostate gland by the 192Ir
implants. By modifying the 192Ir implantation technique, the
initially high rate of rectal ulceration (24%) was reduced to 13% and only 4.5%
of patients required surgical diversion.
C.
Cervical carcinoma
In the United States, cervical carcinoma and other
cancers of the female genital system accounted for about 82,550 new cases and
28,720 deaths in 2004 (Jemal et al, 2004). High-grade, advanced and/or
recurrent gynecological malignancies tend to have a poor prognosis. They are
difficult to cure with conventional external irradiation or any other
therapeutic modality. Thus, patients with gynecological cancers are often
selected for HDR, pulsed-dose-rate and other variations of brachytherapy
(Jensen et al, 1998; Lessard et al, 2002; Rose, 2003). A regimen that includes
low-dose protracted exposure has reportedly been beneficial in at least some of
these cases. Increasing knowledge from pre-clinical studies, some of which are
described below, should eventually help refine these protocols in patients.
Asynchronous and synchronized cervical carcinoma cells
have been exposed to 60Co g-rays at 0.33 and 0.86 Gy/hr (Furre et al, 1999). Clonogenic survival
data indicated the same degree of radiation sensitivity for exposure periods of
less than 20 hr. However, with exposures of >20 hr, a 2-fold greater
radiosensitivity was noted and was found to occur when 80% of the cells had
accumulated in G2. Thus, in this study of cervical carcinoma cells, an inverse
dose-rate effect was demonstrated (i.e. more efficient cell inactivation at
lower compared to higher dose rates) when total radiation doses exceeded 7 Gy.
Other investigators have also demonstrated that the total dose delivered over
an extended time period can influence radiosensitivity (Lamerton and Lord,
1964; Hall et al, 1966).
Dose-rate effects on human adenocarcinomas of the
uterine cervix (NHIK-3025, HeLa, HeLa S3) and human squamous cell carcinomas
(Me180 from the cervix and A431 from the vulva) have been investigated in
xenotransplanted athymic mice (van Oostrum et al, 1990). Intratumorally
implanted cesium-157 (157Cs; 117 MBq) needles 15 mm in length were
used to deliver radiation at 0.5 Gy/hr. Tumor biopsies were taken from 21-160
hr after radiation initiation. One biopsy was taken from tissue that received a
10 Gy dose, whereas other biopsies were taken toward the tumor periphery that
had received total doses of 2-9 Gy. Tumors were also exposed to a much higher
dose rate of 3-4 Gy/min to total doses ranging from 3-10 Gy using a linear
accelerator. Biopsies of these tumors were taken at times corresponding to
biopsy times after the 0.5 Gy/hr irradiation. Changes in tumor cell cycle
distribution were determined by flow cytometry analysis. All five tumor cell
lines were arrested in G2 after the 3-4 Gy/min exposure, whereas only four were
arrested in G2 after 0.5 Gy/hr irradiation. Me180 was the exception that
accumulated primarily in the S phase. Maximum G2 accumulation was related to
cell cycle time and not the dose. Both irradiation conditions resulted in
similar changes in cell cycle progression, but a greater maximum G2
accumulation was observed with the higher dose-rate exposure. In a separate
experiment, the investigators showed that the enhancement of cells in G2
correlated with radiosensitivity as determined by measurements of delay in
tumor regrowth.
In another study, the radiation response of three
cervical carcinoma cell lines (HX155c, HX156c and HX160c) was compared in vitro and in vivo as xenografted tumors (Tonkin et al, 1989). 60Co
g-rays were delivered at continuous rates of 0.03
– 0.05 Gy/min and 0.7 – 1.0 Gy/min. Two of the three cell lines
showed significant low-dose sparing in
vitro and there was a tendency for the in
vivo tumors to reflect a similar pattern. However, there was less tumor
growth delay in vivo than that
predicted from the in vitro data.
The effects of protracted radiation delivered by Mabs
conjugated to radionuclides are being explored in combination with HDR external
beam radiation in pre-clinical studies of gynecological tumors. This technique
is also known as radioimmunotherapy. Success with this combination treatment
was demonstrated in a recent study by Eriksson and colleagues utilizing athymic
mice with s.c. implanted human HeLa Hep2 cervical carcinoma cells (Eriksson et
al, 2003). Treatments with external beam radiation at 3 x 5 Gy and/or 100 mg 131I-labelled Mab against placental
alkaline phosphatase or 131I-Mab against cytokeratin were administered
separately or in combination; specific activity of the Mab was 120-200 Mbq/mg
antibody. Although tumor growth retardation was observed with both external
beam and the radiolabelled Mab, combination treatment enhanced the therapeutic
effects further, resulting in a significant reduction in tumor volume. The
long-lasting tumor growth inhibition was related to increases in tumor necrosis
and apoptosis. The investigators suggest that this combination approach could
increase therapeutic efficiency for epithelial cell-derived tumors in general.
D. Leukemias and lymphomas
Approximately 110,960 individuals were newly diagnosed
and 55,100 deaths occurred in the United States in 2004 owing to hematological
malignancies (Jemal et al, 2004). Collectively, leukemia, lymphoma and multiple
myeloma represent the fourth most common form of cancer. Current radiation and
multiple-agent chemotherapy regimens can be curative in a substantial
percentage of patients with certain forms of these diseases. Nonetheless, more
children die of leukemia than any other disease and the death rates for
non-HodgkinÕs lymphoma and multiple myeloma are increasing in the U.S.A. It
seems possible that implementation of LDR radiation may be beneficial in at
least some of these cases.
In
some studies of hematological malignancies, the apoptotic effect of protracted
radiation has been demonstrated to be independent of p53 status. In one of
these investigations, the Raji model that mimics therapy-resistant human
lymphomas with mutant p53 and increased bcl-2 expression was used (Kroger et
al, 2001). Athymic nude mice bearing Raji lymphoma xenografts were treated with
67Cu-2IT-BAT-Lym-1 antibody (335-500 mCi) and observed for toxicity and tumor response for
84 days. Subsets of animals were euthanized at 3, 6 and 24 hr after therapy so
that tumors could be examined for evidence of apoptosis and for p53, bcl-2,
p21, GADD45, TGF-b1 and
c-myc gene expression and protein level. Apoptosis was greatly increased in the
treated xenografts, whereas bcl-2 gene and protein expression were
substantially decreased. These changes occurred despite only modest cumulated
radiation doses of approximately 0.56 Gy at 3 hr. Apoptosis preceded tumor
regression by 4-6 days and 29% of the tumors were cured by cumulated tumor doses
of ~18 Gy.
Amundson and colleagues have studied gene expression
patterns following LDR and acute g-irradiation of the human ML-1 myeloid leukemia cell line (Amundson et
al, 2003). ML-1 cells have wild type p53 and are relatively responsive to
ionizing radiation in that gene expression changes have been induced with as
little as 0.1 Gy. The study evaluated a wide range of genes by cDNA microarray
after irradiating the ML-1 cells at dose rates of 0.0028 Gy/min to 2.9 Gy/min,
with total doses ranging from 0.02 Gy to 0.5 Gy. Two major clusters of genes
were radiation-induced. The majority of genes in the dose rate-independent
group are known to be involved in cell cycle regulation, whereas the majority
of those in the dose rate-dependent cluster have roles in apoptosis. The
findings were consistent with the significant decline in the percentage of
apoptotic cells with decreasing dose rate that was observed with fluorescence
microscopy. In spite of this, the investigators stated that for the majority of
genes responding to low doses of radiation, a protective dose-rate effect does
seem to apply in the case of this human myeloid leukemia cell line. A slight,
but statistically significant, increase in survival has also been reported for
LX830 mouse leukemia cells with dose rates decreasing from 30 mGy/hr to 6.2
mGy/hr (Furuno-Fukushi and Matsudaira, 1989). In this latter study, no
differences in mutation frequency were associated with dose rate. Other
investigators have found little or no dose-rate effects on survival of
repair-deficient mutants such as mouse lymphoma LYS-s, xrs5, xrs6 and irs20
cells (Evans et al, 1985; Nagasawa et al, 1989; Stackhouse and Bedford, 1993).
E. Other tumor types
In a
study by Williams and co-workers, four human tumor cell lines were evaluated in
colonial survival assays after exposure to protracted irradiation: colon (GEO
and LS174T), squamous cell (SQ-20B) and hepatocellular (HepG2) carcinoma
(Williams et al, 1992). Analysis of cell survival data was performed using a
7-parameter simulation model (Dillehay, 1990). Tritiated water added to cell
culture media was used for ULDR irradiation according to the formula 0.08
mCi/ml = 0.01 Gy/hr, whereas HDR radiation at 1.1 Gy/min was administered using
a g-ray irradiator.
Data for three of the cell lines (GEO, LS174T and SQ-20B) showed diverging
rates of cell kill per unit dose of HDR radiation. With protracted irradiation,
inactivation rates diverged at low doses, but tended to converge at higher
doses. The HepG2 cells, tested only with LDR radiation at 0.03 Gy/hr, exhibited
no redistribution in the cell cycle after 24, 48, or 72 hours of exposure.
Neuroblastoma
is a common malignancy of early childhood, most often arising from the adrenal
medulla. A study of two human neuroblastoma cell lines (HX138 and HX12)
demonstrated no dose-rate effects above 0.02 Gy/min (Holmes et al, 1990). In
addition, when the dose rate was reduced below 0.02 Gy/min, both cell lines
exhibited increased survival.
Clonogenic survival and double-strand DNA breaks were examined
in the RT112 human bladder carcinoma cell line using radiation dose rates
ranging from 0.01 Gy/min to 1.28 Gy/min (Ruiz de Almodovar et al, 1994).
Immediately after irradiation, cell survival increased with decreasing dose
rate, as did the number of double-strand breaks measured by pulsed-field gel
electrophoresis. However, when a 4-hour repair period was allowed after
exposure, all dose rates resulted in approximately the same amount of damage.
The investigators concluded that the level of un-rejoined double-strand DNA
breaks did not correlate with survival at different dose rates, when detected
by this particular gel electrophoresis technique.
Tumor cells vary in terms of their radiosensitivity
dependence on cell cycle distribution, as well as expression of pro-apoptotic
genes (Grdina, 1980; Keng et al, 1984; Brock et al, 1987). In the case of some
tumor cell types, the degree of radiosensitivity has been associated with
levels of pro-apoptotic proteins such as p53 and bax. Ohnishi and collaborators
found that cultured human squamous carcinoma cells primed with g-radiation at 0.001 Gy/min to a total dose of 1.5 Gy
and then challenged with g-rays at 1 Gy/min
exhibited decreased apoptosis and depressed accumulation of p53 and bax
(Ohnishi et al, 2001).
A recent study by Furre and co-workers investigated
the radiosensitivity of T-47D human breast cancer cells (Furre et al, 2003). 60Co
g-rays were delivered at dose rates of 0.37 and 0.94
Gy/hr; cell survival was quantified by the colony formation assay. No increase
in radiation sensitivity was noted when the T-47D cells were accumulated in G2
(i.e. no inverse dose-rat effect). Irradiation
at both dose rates resulted in nearly the same degree of radiosensitivity.
Two-parametric flow cytometry analysis for presence of the retinoblastoma (Rb)
protein and DNA content revealed that ~15% of the cells in G2 had the Rb gene
product bound in the nucleus. The investigators proposed that the Rb protein
could play a role in protecting the G2-arrested cells against radiation-induced
death. In a study of TP53 gene
mutational status and expression levels of related genes (p21, GADD45 and
bcl-2), HBT 3477 human breast carcinoma cells were xenotransplanted into
immunodeficient mice (Winthrop et al, 1997). The animals were injected with 260
mCi of yttrium-90 (90Yt)-DOTA-peptide-ChL6
(Y-90-ChL6), before and after tumor cell implantation and then euthanized at 3,
24 and 48 hr later. Tumor growth rate was also determined. The investigators
found that tumors regressed 4-7 days after treatment with Y-90-ChL6, resulting
in a 79% tumor response that was due to p53-independent apoptosis. In addition,
down-regulation of bcl-2 appeared to be the key to the apoptotic response
induced by the relatively low dose-rate radioimmunotherapy.
Induction of micronuclei was used as an indicator of
apoptosis in Lewis lung carcinoma (LLC) subjected to g-radiation dose rates of 0.34 Gy/min and 1 Gy/min
while growing in mice (Widel and Przybyszewski, 1998). Tumors were excised,
cultured in vitro and scored for
micronuclei at 24-hour intervals. In the range of 0 to 6 Gy, the frequency of
cells containing micronuclei was linearly dependent on dose. However, an
inverse dose-rate effect was evident, with the lower dose rate resulting in a
higher frequency of micronuclei per cell than the higher dose rate. Since the
difference in exposure times between the two dose rates was not great, the
investigators speculated that a differential radiation effect on cell kinetics
during tumor irradiation could not explain the results. Rather, it appeared
possible that the differential effect was dependent upon division delay and
redistribution of cells in the phases of the cell cycle during in vitro incubation. In other words,
they hypothesized that more cells in the higher dose-rate group died in culture
because of interphase death than in the lower dose-rate group and hence the
cells were no longer available for the micronucleus assay.
III.
Dose-rate effects on normal cells
Normal cells respond to ionizing radiation with a
delay in progression through the cell cycle so that DNA damage can be repaired
before DNA replication and mitosis take place. The delay decreases the chance
that genomic instability or mutant phenotypes will appear among the cell
progeny. However, if the damage is too extensive, the cell will be eliminated
because of post-mitotic or apoptotic death. Surviving cells reenter the cell
cycle after various lengths of time, depending upon the radiation dose and the
specific cell type involved. The delay occurs primarily in the G2 phase,
although radiation can also delay cells in G1 and S. Expression of the TP53 tumor suppressor gene is especially
important in these events (Grdina, 1980; Keng et al, 1984; Rauth, 1992; Bristow
et al, 1996). If TP53 is lacking or is
functionally deficient, survival of cells with DNA damage and thus also risk
for subsequent malignancy, is increased (Kato et al, 2002). However, the degree
of radiosensitivity varies substantially among normal cell populations,
especially under conditions of protracted low-dose exposure.
A.
Radiation-induced normal tissue toxicities during radiotherapy
1. Acute versus late effects
With conventional radiotherapy protocols, both acute
and late toxicities are possible (Lichter, 2000; Yamada et al, 2000; Gopal et
al, 2001). Acute effects, seen during and up to 3 months following the end of
treatment, occur primarily in rapidly proliferating tissues such as the skin,
bone marrow and mucosa of the oropharynx, gastrointestinal tract, rectum and
bladder. Erythema, esophagitis, pneumonitis, diarrhea, dysuria and leukopenia
are among the most common manifestations. Late effects occur 3 months or longer
after the end of radiotherapy and can involve virtually any organ or tissue.
Most late reactions include progressively increasing fibrosis, blockage of
blood vessels resulting in tissue anoxia and/or ulceration. Late effects are
generally more serious and more difficult to manage than the acute toxicities.
Eventually, death may occur due to organ failure or other complications.
Development of secondary tumors within the irradiated volume is another
consequence of radiotherapy that is likely to become more prevalent with
increasing survival of cancer patients (Schneider et al, 2000; Strojan et al,
2000; Kranzinger et al, 2001).
2.
Total-body irradiation (TBI)
Injury to normal lung tissue and the gastrointestinal
tract (GI) remains a major problem after total–body irradiation (TBI) in
bone marrow recipients with refractory hematological malignancies and serious
immuno-deficiencies (e.g. severe combined immunodeficiency disease). It was
proposed several decades ago that radiation-induced lung toxicity may be
ameliorated by the use of continuous protracted or fractionated radiation,
since repair of sublethal damage is greater for the lung and GI tract than for
hematopoietic tissue and probably also leukemic cells (Dutreix et al, 1981).
Many preclinical studies have employed localized lung
irradiation, rather than TBI. In a study with mice, radiation was delivered to
the upper body at dose rates ranging from 0.02 to 1.0 Gy/min (Down et al,
1986). A continuous increase in normal tissue tolerance was observed for early
radiation-induced pneumonitis with decreasing dose rate, but a less pronounced
sparing effect was noted for late complications. To evaluate the effects of
adriamycin on radiation-induced pulmonary and upper GI tract toxicity, the
thoracic region of mice was irradiated at dose rates of 0.05, 0.15 and 0.70
Gy/min (Sherman et al, 1982). The beneficial effect of the lower dose rates was
markedly diminished, although still evident when the drug was administered
pre-irradiation. In other words, this study showed that adriamycin can
significantly increase the oral esophageal and pulmonary toxicity of radiation
and can almost abrogate the sparing effect of dose rate. In a mouse model of
bone marrow transplantation, Safwat and colleagues compared TBI delivered at a
rate of 0.08Gy/min with TBI administered at a rate of 0.71 Gy/min, both with
and without cyclophosphamide (Safwat et al, 1996). The drug was administered 24
hr before irradiation and the transplant was performed 4-6 hr after the last
treatment. Lung damage, assessed using ventilation rate and mouse lethality,
was decreased using the lower dose-rate regimen. However, administration of the
drug markedly facilitated the TBI-induced damage. Somewhat unexpectedly, the
combination of protracted radiation plus drug was found to be more toxic than
acute radiation plus drug. In another study, mice given cyclophosphamide before
thoracic irradiation at dose rates ranging from 0.05 Gy/min to 1.0 Gy/min
developed pneumonitis at 4-9 weeks post-exposure (Lockhart et al, 1986).
Without the drug, pneumonitis appeared at 14-16 weeks, regardless of radiation
dose rate. In a rat model of TBI, fractionation had little effect on bone
marrow ablation, but resulted in increased gastrointestinal and renal tolerance
(Moulder and Fish, 1989).
Results from studies in
patients receiving various TBI regimens in association with bone marrow or stem
cell transplantation have generally supported use of LDR or increased
fractionation as a means to minimize normal tissue toxicities, increase the
total dose of radiation that can be safely delivered and improve tumor control
(Evans, 1983; Regnier, 1992; Corvo et al, 1999; Gopal et al, 2001; Song et al,
2003). Radiation therapy at low doses is now commonly employed in cases of
chronic lymphocytic leukemia and low-grade non-HodgkinÕs lymphoma. The
radiation is administered to the entire body at a very low dose per fraction
(0.1 to 0.25 Gy) several times a week until a total dose of approximately 1.5
to 2 Gy is reached. Interestingly, the anti-tumor effects have been reported to
be more pronounced than what would be expected from direct tumor cell
destruction by radiation. It appears that immune enhancement is among the
mechanisms by which TBI results in long-term remissions in the majority of
patients. Pre-clinical studies have demonstrated that TBI up-regulates immune
responsiveness in a number of ways: a) increases IFN-g and IL-2 production; b)
increases expression of IL-2 receptors on T lymphocytes; c) enhances signal
transduction in T cells; d) augments T cell proliferation in response to
mitogens; e) lowers serum corticosterone and increases catecholamine in spleen;
and f) eliminates T cells with immunosuppressive activity (Anderson et al,
1982, 1988; Safwat, 2000a, 2000b).
Low-dose TBI has been
recently tested in combination with IL-2. In one study, mice were inoculated
i.v. with B167F1 malignant melanoma cells on day 0 (Safwat et al, 2003a). A
single whole-body dose of 0.75 Gy was administered on day 7; IL-2 was initiated
on day 8 and given twice daily for 5 consecutive days. Pulmonary tumors were
quantified and examined for tumor-infiltrating cells on day 14. In groups
treated with either modality alone, tumor burden was similar to that in
non-treated controls. However, the combination of low-dose TBI and IL-2
resulted in a synergistic anti-tumor effect. Natural killer (NK) cells and
macrophages were identified as the most likely participants in the highly
significant outcome of combination treatment. In a subsequent study of
malignant melanoma, these same investigators used two doses of TBI and IL-2
(Safwat et al, 2004). Combining TBI with high-dose IL-2 led to a further
significant reduction in tumor and less severe vascular leakage syndrome
compared to high-dose IL-2 alone. In this case, therapeutic efficacy was
associated with the number of tumor-infiltrating NK cells. The investigators
concluded that the combination treatment was not only more effective, but also less toxic than IL-2 alone. Although
very few human studies have been conducted in this area, data suggest that
low-dose radiation-induced immune defense mechanisms may be operating (Safwat
2003b). Based on these types of data, some have suggested that administration
of low-dose TBI may be beneficial for patients with AIDS (Shen et al, 1989;
Shen et al, 1997). In contrast, TBI has also been associated with enhanced
tumor progression (Duhrsen and Metcalf, 1988; Gridley et al, 1997). The
discrepancies in reported data may be related to tumor type and load, as well
as the dose rates and total doses of radiation utilized.
3. Central nervous system (CNS)
Radiotherapy for
neoplasms of the brain inevitably results in some damage to neurons. The damage
can trigger a series of events, leading to destruction and malfunction of a
relatively large volume of tissue due to secondary degeneration (Ikonomidou and
Turski, 1996; Yoles and Schwartz, 1998). Side effects ranging from headaches,
dizziness, nausea and cognitive defects to development of secondary CNS
neoplasms following treatment remain problematic and are likely to become more
obvious with increased survival times (Leibel SA and Sheline 1987; Schultheiss
et al, 1995; Strojan et al, 2000; Kranzinger et al, 2001). The success of
anti-inflammatory drugs such as corticosteroids in controlling edema and
increased intracranial pressure suggests that cells of the immune system play a
role in the development of at least some of the observed toxicities.
Corticosteroids have a number of non-specific anti-inflammatory and
immunosuppressive properties including: a) they inhibit neutrophil migration to
sites of tissue damage and thus minimize the level of neutrophil-derived
vasoactive amines that increase vascular permeability and produce edema; b)
they suppress IL-1 production by cells of the monocyte/macrophage lineage, a
cytokine that is needed for T cell activation: and c) they impair synthesis and
secretion of IL-2 by T lymphocytes, which in turn reduces the ability of the T
cells to proliferate and produce pro-inflammatory cytokines.
For many decades, the CNS
was considered to be an immunologically privileged site, with little or no
interaction occurring between the immune and central nervous systems; if immune
activity did occur, it was thought to be detrimental (Streilein, 1993; Popovich
et al, 1996). However, a series of recent studies have demonstrated that
recruitment of systemic T lymphocytes to the injured site helps the innate
branch of the immune system to ward off toxicity (Moalem et al, 1999; Schwartz
and Cohen, 2000; Fisher et al, 2001; Kipnis et al, 2001, 2002). In contrast to
healthy tissue, the injured CNS is more accessible to circulating lymphocytes
because of blood-brain barrier breakdown and expression of adhesion molecules,
chemokines and major histocompatibility complex (MHC) class II molecules. The
in-migrating T cells belong to the Th1 subset that secretes cytokines such as
IL-2 and IFN-g. In addition, they are autoreactive and respond to specific ÔselfÕ
antigens (e.g. anti-myelin protein) that are presented to them by activated
microglia. Indeed, it has been demonstrated that rats and mice that are either
deficient in mature T cells or that lack auto-reactive T cells lose their
ability to withstand injury to the CNS (Kipnis et al, 2000; Schori et al,
2001). The existence of a protective role for the immune system has been
strengthened by the demonstration that passive transfer of a subpopulation of T
suppressor cells (i.e. the naturally occurring regulatory CD4+/CD25+
T cells) can eradicate irradiation-induced Th1 cell-derived neuroprotection
(Kipnis et al, 2002). Most recently, a study was done to determine whether g-radiation benefits
neuronal survival by alterating immune system status (Kipnis et al, 2004). Mice
and rats were subjected to optic nerve crush or contusive injury to the spinal
cord. Total-body or total-lymphoidal irradiation (3.5 Gy) resulted in
significant increases in neuronal survival (in some cases more than 3-fold) and
more rapid recovery from injury. The beneficial effects were noted when
radiation was administered up to 3 days post-injury.
4.
Mutations and carcinogenesis
Numerous studies of dose-rate effects on mutagenesis
have been performed using human and rodent lymphoid cells (Lorenz et al, 1993;
Lorenz et al, 1994; Amundson and Chen, 1996; Furuno-Fukushi et al, 1996). The
hypoxanthine-guanine phosphoribosyl transferase (HPRT) and thymidine kinase
(tk) loci have arguably received the greatest attention. In a study of mutation
size at the HPRT locus in human lymphoblastoid WI-L2-NS cells, an inverse
dose-rate effect was found after a total dose of 4 Gy (Colussi and Lohman,
1997). Significantly larger deletions were produced by LDR exposure than with
HDR exposure. Since the majority (>60%) of cells irradiated with HDR were in
G1 and those irradiated with LDR went through the S-phase and on into G2, the
investigators proposed that the difference in mutation size may be related to
the stage of the cell cycle. Other studies have demonstrated that decreasing
the dose rate results in an inverse dose-rate effect as manifested by increased
mutagenesis (Furuno-Fukushi et al, 1988; Crompton et al, 1990; Amundson and
Chen, 1996). In contrast, some investigators have reported that protracted
radiation exposures protect against mutation induction
both in vitro (Evans et al, 1990) and
in vivo (Lorenz et al, 1994) or have
no significant effect compared to acute irradiation (Furuno-Fukushi et al,
1996). In some cases, discrepancies have been observed between in vitro and in vivo data (Lorenz et al, 1993). Reports by Furuno-Fukushi
and colleagues using non-transformed, near-diploid m5S mouse cells demonstrated
that cell proliferation during protracted irradiation has a strong influence on
mutagenesis (Furuno-Fukushi et al, 1993). In plateau-phase cultures, lowering
the dose rate from 30 Gy/hr to 13 mGy/hr resulted in an increase in cell
survival and a marked decrease in mutation frequency. However, when the cells
were in log-phase culture, the magnitude of the dose-rate effect was not nearly
as marked, especially when the total dose was below 5 Gy. An interesting study
of mutagenesis was recently performed in which chronic low-dose rate g-irradiation was used to mimic the environment
experienced by residents during the Chernobyl accident (Wickliffe et al, 2003).
Big Blue‰ mice were exposed
to g-rays for 90 days, resulting in a cumulative dose of 3
Gy (0.0014 Gy/hr). No significant increase in mutation frequency was observed
in the irradiated mice based on DNA analysis of liver tissue (Big Blue‰ Transgenic Rodent Mutagenesis Assay System).
The above-mentioned studies, as well as others,
indicate that variations in experimental conditions may at least partly account
for the apparent contradictions that have been noted in radiation-induced
mutagenesis. Overall, the preponderance of evidence indicates that the risk for
radiation-induced mutagenesis in somatic and germ line cells decreases with
decreasing dose rate (Vilencheck and Knudsen, 2000).
B.
Radio-adaptive response
The consensus that radiation is harmful to normal
cells has prevailed for many decades. Among the most serious consequences are
immunodeficiency, mutations and development of malignancies such as leukemia
and multiple myeloma (reviewed by Dainiak 2002). Numerous studies of
radiation-induced chromosomal and DNA aberrations have been performed on
lymphocytes and lymphoid cells (Hofer et al, 1994; Kronenberg, 1994; Moiseenko
et al, 1997; Wu et al, 1997, 1999; Blakely and Kronenberg, 1998; Durante et al,
1998, 1999, 2000, 2002; Yamada et al, 2000; Gauny et al, 2001; Grosovsky et al,
2001; Holl et al, 2001; Wiese et al, 2001; Schulz-Ertner et al, 2002). These
studies have revealed important radiation-induced genomic abnormalities, as
well as variations due to differences in radiation quality. Although lymphoid
organs have long been known to be highly radiosensitive, the susceptibility of
different lymphocyte populations varies greatly, possibly owing to differences
in repair mechanisms, maturation stage, activation state and/or innate rate of
proliferation (Stefani and Schrek 1964; Miller and Cole, 1967; Anderson and
Warner 1976; Anderson et al, 1977, 1988; Prasad 1995). An additional important
observation is that irradiation can up-regulate many genes, including some that
encode cytokines that can modify cellular responses to radiation (Hallahan et
al, 1993; Hallahan, 1996; Barcellos-Hoff, 1998;).
It is clear that radiation, when delivered at a slow
continuous rate or by fractionation may have strikingly different effects
compared to the same dose delivered acutely. Early studies demonstrated that
monkeys could tolerate whole-body exposures up to 19 Gy with minimal
suppression of the hematopoietic system when the radiation was delivered at a
rate of 1 Gy/year (Spalding et al, 1972). The 19 Gy is approximately three
times the lethal dose when applied acutely. Soon thereafter, it was reported
that protracted radiation exposure may induce beneficial effects (i.e.
radio-adaptation, previously known as ÔhormesisÕ) (Anderson and Warner, 1976;
Anderson et al, 1977). The radio-adaptive response has gained much attention in
recent years because of its obvious importance in setting accurate guidelines for
radiation-associated human health risks, in basic radiobiology research and now
also in radiation therapy. The phenomenon has been extensively discussed in a
number of publications (Bhattacharjee and Ito, 2001; Feinendegen 2003;
Pollycove and Feinendegen, 2003). In this review, only a few highlights of
special interest are mentioned.
Various endpoints have been used to detect and
quantify radio-adaptation, including chromosome aberrations (Shadley et al,
1987; Wolff et al, 1988; Sankaranarayanan et al, 1989; Farooqi and Resavan,
1993), mutations and DNA strand breaks (Shadley and Wolff, 1987; Kelsey et al,
1991; Rigaud et al, 1993), micronucleus formation (Azzam et al, 1994) and cell
survival (Olivieri et al, 1984; Yoshida et al, 1993; Sasaki, 1995). In many of
these studies, low-dose irradiation of lymphocytes has been found to minimize
the harmful effects of a subsequently delivered high dose of radiation. For
example, although lymphocytes from individuals occupationally exposed to
chronic doses of radiation have higher frequencies of spontaneous micronuclei
than non-exposed individuals, after 1 and 2 Gy irradiation of the lymphocytes in vitro this frequency is lower for the
radiation workers (Gourabi and Mozdarani, 1998). It has also been reported that
low-dose irradiation can enhance the production of IL-1 by lipopolysaccharide
(LPS)-stimulated splenocytes, responsiveness to T cell mitogens (Ishii and
Watanabe 1996) and expression of IL-2 receptors on the surface of peripheral
blood lymphocytes (Xu et al, 1996). Many of these types of reports indicate
that a significant radio-adaptive response is measurable within a few hours
after low-dose priming (Farooqi and Resavan, 1993; Ishii and Watanabe, 1996;
Park et al, 2000; Venkat et al, 2001).
With intact mammalian
models, radio-adaptation in immune cells has been shown to protect mice
injected with the Friend leukemia virus, a member of the retrovirus family that
includes HIV-1 (Shen et al, 1989; Wolff et al, 1989; Fujiki and Suganuma,
1994). It has also been noted that the onset of thymic lymphoma is
significantly delayed in Swiss mice
pre-conditioned with 0.01 Gy and then acutely irradiated with 2 Gy
(Bhattacharjee, 1996). Similar results have been obtained for acute myeloid
leukemia (Mitchell et al, 1999) and some transplanted solid tumors in mice
(Bhattacharjee and Sarma, 1999). In one very recent report, mice were subjected
to single low-level exposures of 0.1 Gy or 0.2 Gy X-rays and injected i.v. 2 hr
later with syngeneic L1 sarcoma cells (Cheda et al, 2004). Pre-treatment with
either dose of radiation significantly reduced the number of tumor colonies in
the lungs compared to the non-irradiated counterparts. In addition,
significantly enhanced NK cell cytotoxic activity was observed in spleens from
the irradiated animals and elimination of the NK cells by injection of
anti-asialo GM1 antibody totally abrogated the radiation-induced
tumor-inhibitory effect. Studies by other investigators support these findings.
Suppression of pulmonary nodule development with single doses of X-rays (0.05
Gy to 0.15 Gy) 24 hr before i.v. injection of B16 melanoma and Lewis lung
cancer cells has been reported in mice (Cai, 1999). Hashimoto and co-workers
have shown that lung and lymph node metastases are decreased and that metastatic
foci are infiltrated by lymphocytes in rats exposed to 0.2 Gy g-rays
14 days after s.c. injection of hepatoma cells (Hashimoto et al, 1999). In this
latter study, in vitro irradiation of
the tumor cells or localized irradiation of tumor in vivo at the same dose did not affect either primary tumor growth
or degree of spontaneous metastases. Irradiation of mice with X-ray doses of
<0.2 Gy has also been reported to suppress local tumor growth when malignant
cells are injected after the radiation exposure (Anderson et al, 1982; Cai,
1999). Some investigators have suggested that the enhanced anti-tumor effect
may be related to secretion of TNF-a
and other cytokines by cells of the monocyte-macrophage series that become
activated by debris due to radiation-induced damage (Hallahan et al, 1989;
Sherman et al, 1991; Weichselbaum et al, 1991). TNF-a may add to the lethality of
radiation because it has both direct and indirect anti-tumor effects.
Although radio-adaptation
was not specifically addressed, our previous studies have demonstrated that
s.c. growth of Lewis lung carcinoma in C57BL/6 mice is consistently slower when
the animals are exposed to 3 Gy g-rays
2 hr prior to tumor cell implantation (i.e. representing a small neoplastic
focus that appears after the irradiation event has taken place) and that the
anti-tumor effect was related to immune enhancement during repair of normal
tissue damage (Miller GM et al, 2002, 2003a, 2003b). The data also showed that
a dramatic expansion of NK cells occurred in the blood and spleen of
tumor-bearing animals 10 days after irradiation (28.0 x 105 NK
cells/spleen in irradiated mice compared to 8.9 x 105 NK
cells/spleen in non-irradiated controls). Enhanced production of IL-12 and
IL-18 by spleen cells was consistent with augmentation of the NK cell response.
Significant reductions in TGF-b1
and vascular endothelial growth factor (VEGF), both of which are associated
with immune suppression, were also noted. Enhanced NK cell activity after
total-body irradiation with 0.075 to 0.5 Gy X- or g-rays has been reported by other
investigators (Kojima et al, 2002, 2004; Liu et al, 1994). The important role
of NK cells in nonspecific immune surveillance against aberrant cells and
metastatic growth has been well established (Talmadge et al, 1980; Hanna, 1985;
Wiltrout et al, 1985; Moretta et al, 1994; Reyburn et al, 1997; Barao and
Ascensao, 1998). These findings are consistent with the radiation-induced
ÒdangerÓ signal originally proposed by Matzinger in 1994 and recently reviewed
by Friedman (2002). Based on studies such as those above, it has been suggested
that low-dose whole-body irradiation may be useful in treating some cancer
patients (Pollycove and Feinendegen, 2000). However, it should be mentioned
that the incidence of radiation-induced carcinogenesis increases in humans when
doses exceed approximately 0.3 Gy (Pollycove and Feinendegen, 2003).
Radio-adaptation has also
been reported in normal cells other than those of the immune system. Broome and
colleagues demonstrated that exposure of cultured AG1522 human fibroblasts to
total doses ranging from 0.0001 Gy to 0.5 Gy at dose rates ranging from 0.001
to 0.003 Gy/min prior to a challenge dose of 4 Gy g-rays exhibited reduced
frequency of micronuclei (Broome et al, 2002). There was no significant
difference in the degree of protection induced by the two extremes of total
doses used and a similar degree of protection was induced with protracted
exposure to g-rays and 3H beta particles. These latter findings
demonstrated that doses as low as one track per cell (0.0001 Gy) produced the
same maximum adaptive response as did doses that resulted in many tracks per
cell (0.5 Gy) and that the two types of radiations were similar in this
respect. In addition, induction of radio-adaptation in the fibroblasts occurred
even when the cells were incubated at 0o C during delivery of the
priming dose, a temperature at which DNA repair and other metabolic processes
are inactive.
In a study of human
erythrocytes subjected to g-radiation, identical total doses
delivered in a single fraction or split into two identical fractions with a 3.5
hr interval between exposures, resulted in a 2.4-fold reduction in hemolysis
when the split doses were administered (Koziczak et al, 2003). The results also
suggested that the reduced damage to the red blood cells occurred because of a
decrease in the level of damage to membrane lipids. An interesting study of
genetic damage in erythrocytes in the bone marrow of SHK mice has been recently
performed (Zaichkina et al, 2003). The effect of low-dose g-radiation (0.1 and 0.2
Gy total doses at 0.125 Gy/min) on high-dose (1.5 Gy total dose at 1 Gy/min)
radiation-induced and spontaneous levels of cytogenetic damage was evaluated
over the entire lifetime of the animals. The amount of micronucleated
polychromatic erythrocytes in primed, primed and challenged and control groups
was assessed at various time points. A single low-dose exposure induced
cytogenetic radio-adaptation at 1, 3, 6, 9 and 12 months after priming,
regardless of mouse age at the time of priming irradiation. In addition, the
low-dose priming exposure resulted in decreases in cytogenetic damage to a
level below the spontaneous rate at the end of the lifetime (20 months) of the
animals. These data demonstrated that the mechanisms underlying
radio-adaptation in erythrocytes protect against chromosome damage induced by
high-dose irradiation and appear to also minimize spontaneous mutagenesis
during aging.
Although the mechanisms underlying radio-adaptive
responses remain unclear, a possible scenario has been proposed by Ikushima and
colleagues (1996.) and reviewed by Bhattacharjee and Ito (2001). In this model,
low dose pre-irradiation damages a small amount of nuclear DNA, ultimately
leading to enhanced capacity to repair serious DNA damage induced by a
subsequent high dose irradiation event. In support of this possibility are
recent studies demonstrating that continuous exposure to X-rays at a low-dose
rate leads to no detectable misrejoining of double-strand DNA breaks in
cultured mammalian cells (Kuhne et al, 2002). This finding suggests that the
probability of inappropriate repair decreases dramatically when the breaks are
separated in time and space. Using cell lines deficient in non-homologous
end-joining, the investigators concluded that this is an efficient pathway for
correct rejoining of separated broken ends, but that it generates genomic
rearrangements if the breaks are close in time and space. In this same study
there was no significant decrease in double-strand DNA misrejoining after
exposure of the cells to fractionated doses of alpha particles, indicating that
radiation quality may be a significant factor in determining whether or not
protracted low-dose radiation results in protection.
However, the overall evidence for more efficient DNA
repair in radio-adaptation is largely indirect and efforts continue to identify
other mechanisms. For example, Takahashi et al, reported that splenocytes from
C57BL/6N mice primed with whole-body irradiation to a total dose of 1.5 Gy g-rays delivered at a dose rate of 0.001 Gy/min over 25
hr, exhibited significant suppression in p53, bax and apoptosis after a 3 Gy
challenge dose of X-rays delivered at a high-dose rate (1 Gy/min) (Takahashi et
al, 2001). In subsequent studies, these same investigators demonstrated that
the apoptosis induced by acute 3 Gy irradiation was significantly suppressed in
the splenic white pulp of wild-type, but not SCID (severe combined
immunodeficiency), mice and that DNA-dependent protein kinase activity may play
a major role in the radio-adaptive response following pre-irradiation at low
doses (0.15 - 0.6 Gy) (Takahashi et al, 2002, 2003). Others have reported that
protein kinase C-mediated signaling may be a key step for transducing the low
dose-induced protective signal (Rigaud and Moustacchi, 1996). Using chromosomal
aberrations as the indicator of damage in human lymphocytes, it has been
demonstrated that the anti-mutagenic action observed with low-dose irradiation
is similar to that seen with interferon pre-treatment (Tskhovrebova et al,
1995; Makedonov et al, 2000). These results suggest that priming with low-dose
radiation and the action of IFN-g may induce common pathways of protection. Some reports indicate that
reactive oxygen species play an important role in inducing radioprotection. In
the body, oxygen radicals are generated not only by the direct effects of
ionizing radiation, but also by inflammatory cells that migrate to the site of
tissue damage (Gridley et al, 2005). Feinendegen has recently proposed that the
site, type and size of oxygen radical bursts, as well as the time interval
between them, may be an integral component of the mechanisms leading to
cellular radio-adaptation (Feinendegen, 2002). Reactive oxygen species at low
concentrations appear to induce cellular protection, whereas the reverse is
true at high concentrations. In a study of bystander effects, Iyer and Lehnert
transferred supernatants from human lung fibroblasts (HFL-1) irradiated with a
0.01 Gy dose of g-rays to non-irradiated
HFL-1 cells (Iyer and Lehnert, 2002). When the unirradiated cells were
subjected to 2 and 4 Gy doses of acute g-radiation, clonogenic survival was enhanced. The radio-adaptive
bystander effect was preceded by an increase in intracellular oxygen radicals,
an increase in the redox and DNA repair protein AP-endonuclease and a decrease
in p53 protein. Studies with plants suggest that exposure to very low-dose-rate
g-rays (66 mSv/hr or approximately 66 mGy/hr) leads to
an efficient induction of superoxide dismutase and other enzymes that protect
against reactive oxygen species (Zaka et al, 2002).
C. General population
Studies
of human populations previously exposed to various radiation doses and dose
rates may provide information that is useful in radiotherapy, especially with
respect to effects on cells that constitute the immune system. The functions of
these cells include continuous surveillance for aberrantly (including
neoplastically) transformed cells, as well as destruction of tumor cell targets,
and hence they may contribute to the final outcome in radiotherapy patients. In
addition, preservation of the bone marrow (hematopoietic system) is of great
importance in mitigating the risk for infection, anemia, and other
complications in cancer patients. Studies of survivors after accidental
irradiation events, such as those that took place at Three Mile Island and
Chernobyl (Lenschow et al, 1996; Thompson,
1994), may help elucidate dose and dose rate effects on bone marrow and other
normal cells and tissues. Furthermore, in recent years the possibility of
radiation exposure due to a nuclear (radiological) terrorism attack has come to
the forefront of public and government attention. There is now great urgency to
identify the best radioprotectants already available, as well as develop and
validate new and better compounds. It is very likely that one or more of these
radioprotectants will become incorporated into radiotherapy regimens for normal
tissue protection before, during, and perhaps even after treatment to minimize
damage due to oxygen radicals released by inflammatory cells.
Much attention has been paid to the lymphocytes, especially the T cells, because they
regulate the bodyÕs most sophisticated immune defenses. Loss or malfunction of
these cells can lead to dire consequences as exemplified by AIDS patients and
organ transplant recipients. Studies of atomic bomb (A-bomb) survivors have
revealed significant decreases in mature T lymphocytes, T helper (Th) cells
(but not T cytotoxic, B, or NK cells) (Kusunoki et al, 1998), frequency of T
cells capable of secreting type 1 cytokines (Kusunoki et al, 2001), T cell
reactivity to mitogens (Akiyama et al, 1983) and T cell response to allogeneic
cells (Akiyama et al, 1989). Signs of T cell impairment, including increased
reactivation of the potentially oncogenic Epstein-Barr virus (EBV), have been
reported in these individuals (Kanamitsu et al, 1966; Kato et al, 1980; Akiyama
et al, 1989, 1993). Yamoaka and associates recently demonstrated that A-bomb exposure
induced long-lasting deficits in both na•ve T helper and T cytotoxic cell
populations, along with increased proportions of memory T cells belonging to
these subsets (Yamoaka et al, 2004). These findings indicate poor maintenance
of T cells that are newly generated post-exposure. Additional data in support
of defective T cell activities come from studies of persons exposed to fallout
from the nuclear power plant accident at Chernobyl (Lukjanova et al, 1995;
Stepanova et al, 1995; Chernyshov et al, 1997). In one of these investigations
it was found that long-lasting depletion in the Th1 subset exists concomitantly
with excessive proliferation of the Th2 subset and that an activating stimulus
may be necessary to reveal radiation-induced immune disturbances (Dainiak,
2002). Studies of Belarussians residing near Chernobyl report differences in
gene expression patterns for subjects exposed to >10 mSv compared to those
receiving <10 mSv (Karkanitsa et al, 2000). In these investigations, the
upregulated genes were primarily those encoding proteins associated with
mitotic and apoptotic death in T cells and monocytes.
Emphasis has also been placed on radiation-induced
mutations that lead to carcinogenesis. In vitro
exposure of human peripheral blood lymphocytes to low doses of X-rays (0.25 to
1.5 Gy) at a dose-rate of 1 Gy/min resulted in increased expression of several
proto-oncogenes at 5 hr and 17 hr post-exposure (Miller AC et al, 2002). The
up-regulation was especially striking for c-Haras. The investigators suggested
that c-Haras may be useful as an early biomarker indicative of radiation
exposure. In A-bomb survivors, increased incidence of leukemias, especially
chronic myelogenous leukemia (CML) and other myeloproliferative diseases has
been reported (Ichimaru et al, 1991). The threshold for CML in Hiroshima is
thought to be between 0.09 Gy to 0.5 Gy, whereas for acute leukemia the
threshold appears to be approximately 1 Gy. Some epidemiological studies of
low-level exposures have concluded that cancer incidence and mortality among
residents living in high versus low background areas is not significantly
different (Jagger, 1998; Luckey, 1999).
The effects of long-term, low-level g-irradiation among individuals exposed in
radiocontaminated buildings has also been studied. Increased frequencies of
various chromosomal aberrations, especially breakpoints, inversions and
translocations on chromosomes 7 and 14, have been reported (Hsieh et al, 2002).
This is of interest, since the genes that code for the T cell antigen receptor
and the heavy chains of antibodies are found on these two chromosomes. Thus,
mutations in these chromosomes could lead to significant immunodeficiency.
Some additional findings indicate that doses as low as
0.05 Gy to 1 Gy increased the incidence of cardiovascular disease in both
A-bomb survivors and victims of the Chernobyl accident (reviewed by Trivedi and
Hannan, 2004). Furthermore, wounds heal more slowly under conditions of
radiation exposure, with the delay in wound healing being related directly to
the dose of radiation (Ran et al, 2003; Shi et al, 2003). During wartime, large
numbers of military personnel may experience prolonged exposure to radiation
that occurs simultaneously with wounding. Astronauts are inevitably exposed to
chronic irradiation and may also become injured while on board a spacecraft.
Combined injury also occurs when surgery and radiation are used for cancer
therapy. The mechanisms by which radiation delays wound healing are not clear,
but may include reduction in the number of platelets and inflammatory and other
tissue-repairing cells that accumulate at the injured site (Qu et al, 2003).
IV.
Conclusions
It is often stated that
the major goal of cancer radiotherapy is to select a treatment regimen that has
the highest probability for uncomplicated cure. A large amount of data suggests
that differences in radiosensitivity between tumor and normal cell populations
could be exploited to achieve a substantial increase in the therapeutic ratio.
The overall implication of the discussed studies is that increased control of
at least some types of cancers may be achieved by combining protracted
irradiation with standard external beam therapy. However, at this point in
time, it is difficult to predict with a high degree of certainty the tumor
types for which this treatment approach may be beneficial and those for which
the strategy may be a poor choice.
Induction of
hyper-radiosensitivity in tumor cells by protracted radiation exposure is
clearly not a universal phenomenon. In addition, there appears to be lack of a
consistent trend in the extent that tumor cells repair sublethal
radiation-induced damage compared to normal cells, although a correlation
between the degree of sublethal damage repair and radioresistance does appear
to exist. Using a series of assumptions and mathematical modeling, Hahnfeldt
and Hlatky have demonstrated that there is a tendency toward an inverse
dose-rate effect even when heterogenous and cycling cell populations are
exposed to low-LET radiations (e.g., photons and protons) in a protracted
manner (Hahnfeldt and Hlatky, 1998). However, the mechanisms by which
protracted irradiation increases tumor cell radiosensitivity in relation to
acute iurradiation remain elusive. A recent publication by Marples and
colleagues elegantly summarizes the most pertinent literature in this regard
(Marples et al, 2004). The paper also proposes a three-component model
consisting of damage recognition, signal transduction and damage repair.
Undoubtedly, many questions still remain unanswered. Especially intriguing is
why some tumor cells fail to exhibit hyper-radiosensitivity and why there is
inconsistency between accumulation in the radiosensitive G2 phase of the cell
cycle and hyper-radiosensitivity. The mechanisms underlying the radio-adaptive
response and the significant anti-tumor effect following whole-body irradiation
that exceeds what is seen when the same dose is delivered only to the tumor are
phenomena that also warrant further investigation. From the information currently
available, it appears likely that hyper-radiosensitivity and adaptation leading
to increased radioresistance are distinct examples of ÔactiveÕ responses to
low-dose radiation exposure that are associated, at least partly, with the rate
of DNA damage and the extent of DNA repair (Joiner et al, 1999; Marples et al.
1997). With the rapid progress currently on-going in elucidating
radiation-induced chromosomal events, genes that control DNA repair and signal
transduction pathways, incorporation of protracted low-dose radiation in cancer
therapy may eventually become common in the clinic.
We suggest that the data, when taken in toto, indicate that future
application of reduced dose-rates in the clinic may have several important
roles: 1) direct tumor cell cytotoxicity that is greater than what is observed
with acute irradiation; 2) induced changes that result in greater tumor control
by HDR external-beam radiation; 3) radio-adaptation in normal cell populations
that decrease risk for complications; and 4) up-regulation of anti-tumor immune
responses. Increased knowledge of mechanistic effects of reduced dose-rate
irradiation on both tumor and normal tissues and the subsequent impact on the
therapeutic ratio is needed for future clinical utility.
Finally, we accept that the database that we have
reviewed is complex and currently it is difficult to proceed to clinical trials
with confidence in the application of low dose-rate therapy. However, we do
suggest that there are laboratory and clinical research projects that should be
undertaken with some priority. First, we need increased knowledge of
mechanistic effects of reduced dose-rate irradiation on tumor cells, especially
defining the molecular processes that are shared by induced hypersensitivity,
adaptive response, and their contribution to cell killing by mitotic and
apoptotic processes. Further, it is important that these observations be
extended to model tumor systems such as xenografts growing in the nude mouse to
determine whether cell-based observations in
vitro can be extended to in vivo
response of model tumors comprised of cells that do or do not exhibit low dose,
low dose-rate radiosensitivity. We
think that certain clinical studies should be considered. First, the
combination of low dose-rate irradiation delivered by brachytherapy and
radiolabelled antibody therapy with external beam high dose-rate radiotherapy
is immediately feasible. Second, as soon as variation of response to low
dose-rate irradiation and to combined LDR and HDR of brain tumors can be
predicted for such tumors with some confidence, then such therapy should be
given priority. Also, radioresistant tumors such as certain sarcomas, when
located in sites accessible to direct injection of carriers of radionuclides
could be considered for LDR/HDR therapy.
Last, but not least, a better understanding of the response of normal
tissues and the subsequent impact on the therapeutic ratio is needed for future
clinical utility.
Acknowledgements
We thank Larry E. Dillehay, Ph.D., Research Associate
and Director of Experimental Radiators in the Department of Radiation Oncology
& Molecular Biology at Johns Hopkins School of Medicine for use of data
depicted in the figure and William Preston, Ed.D. for expert editorial
assistance.
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Daila S. Gridley
