Cancer Therapy Vol 3, 525-530, 2005
Incidence of gastrointestinal toxicity during estramustine
phosphate therapy for prostate cancer is associated with the single-nucleotide
polymorphisms in the cytochrome P450 1A1 (CYP1A1) gene
Mohammed Rafiqul Islam Mamun1, Motofumi Suzuki1,
Satoru Takahashi1, Kazuo Hara2, Takeshi Ozeki3,
Yasuhiko Yamada3, Takashi Kadowaki4, Yoshitsugu
Yanagihara5, Shuji Kameyama6, Yoichi Minagawa Ito7,
Takumi Takeuchi1 and Tadaichi Kitamura1,*
1Department
of Urology, Graduate
School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
2Department of Clinical Bioinformatics,
Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
3Department
of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University
of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan
4Department
of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
5Department
of Pharmacy, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
6Department
of Urology, Kanto
Medical Center NTT EC, 5-9-22 Higashigotanda, Shinagawa, Tokyo 141-8625, Japan
7Department of Biostatistics / Epidemiology and
Preventive Health Sciences, School of Health Sciences and Nursing, The University
of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
__________________________________________________________________________________
*Correspondence: Tadaichi
Kitamura, M.D., Ph.D., Professor and Chairman, Department of Urology, Graduate
School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-8655, Japan; Phone: +81-3-5800-8662, Fax: +81-3-5800-8917; E-mail: KITAMURA-DIS@h.u-tokyo.ac.jp
Key words: Estramustine
phosphate, CYP1A1, Gastrointestinal toxicity, Prostate cancer, Tailor-made
medication
Abbreviations:
confidence interval, (CI); Cytochrome P450, (CYP); Estramustine phosphate,
(EMP); estramustine, (EaM); estromustine, (EoM); Gastrointestinal toxicity,
(GIT); intervening sequence, (IVS); luteinizing-hormone releasing-hormone
agonist, (LH-RHa); odds ratio, (OR); polymerase chain reaction, (PCR); single
nucleotide polymorphisms, (SNPs)
Mohammed Rafiqul
Islam Mamun and Motofumi Suzuki had equal contribution to this study.
Summary
Gastrointestinal
toxicity (GIT) is observed frequently during estramustine phosphate (EMP)
therapy in prostate cancer patients. This adverse effect often deteriorates the patientsÕ compliance and quality of life, which results in drug
discontinuation. The CYP1A1 gene is polymorphic and involves in the metabolism of EMP. Polymorphisms of
the CYP1A1 gene might have a role to modulate the metabolism of EMP and convert
patientsÕ ability to comply with the drug toxicities. We performed
genotyping of the CYP1A1
gene to reveal interindividual difference of GIT
associated with EMP therapy. The study enrolled 126 patients with
untreated advanced prostate cancer. Low-dose of EMP was administered orally. Genotyping of m1, m2 and IVS1-728 polymorphisms of the CYP1A1 gene was performed by PCR-based
direct sequencing method. In the multivariate
analysis, GIT risk was increased significantly in the major
allele homozygous genotypes of m1 and IVS1-728 SNPs compared with the
heterozygous and minor allele homozygous genotypes (T/T genotype of m1, odds ratio (OR), 2.69; 95% CI, 1.24 to 5.96; P = 0.01; and
G/G genotype of IVS1-728, OR, 3.31; 95% CI, 1.52 to 7.47; P < 0.01). Haplotype study showed that the risk of GIT was
enhanced approximately 12 times higher when ÔTÕ nucleotide in m1, ÔAÕ
nucleotide in m2 and ÔGÕ nucleotide in IVS1-728 locus are present in a same
allele (OR, 11.86; 95% CI, 3.61 to 39.02; P < 0.01)
compared with the other allelic combinations. This study demonstrated that m1,
m2 and IVS1-728 polymorphisms in the CYP1A1 gene were significantly associated
with GIT during EMP therapy in prostate cancer patients. Genotyping of these
polymorphisms prior to commence the EMP therapy will be a useful method to select the patients with a risk of GIT and to improve patientsÕ
compliance and quality of life.
Estramustine phosphate (EMP) is a chemoendocrine agent
that was applied for the treatment of
prostate cancer in the 1970s. Nowadays, usually it is used
for the treatment of hormone refractory prostate cancer. Recently, synergy between EMP and other antimicrotubule agents
(i.e. paclitaxel and docetaxel) in the treatment of androgen-independent
prostate cancer has been assessed and the clinical efficacy of EMP has been
re-evaluated (Vaishampayan et al, 2002; Oudard, 2005).
Gastrointestinal toxicity (GIT) is a frequent adverse effect during EMP therapy in prostate cancer
patients. GIT
includes anorexia, heartburn, nausea and vomiting. Recently, we conducted a
clinical trial of low-dose EMP monotherapy for previously untreated prostate
cancer. The object is to achieve the goal of lowering the incidence of adverse
effects without compromising the therapeutic efficacy. We found 93.4% of
prostate specific antigen (PSA) response rate (Kitamura, 2002), which was
comparable with that of conventional dose EMP therapy. However, incidence of
the toxicity remained rather high as 39.5% and discontinuation rate was 32.1%.
Individual susceptibility to the adverse effects perhaps linked with the
polymorphisms of the enzymes encoding genes that are related to the metabolism
of this drug.
Figure 1 is a schematic diagram showing the metabolic pathway of EMP. EMP consists of 17b-estradiol bound to nor-nitrogen mustard. After ingestion, EMP undergoes rapid dephosphorylation to yield
estramustine (EaM), and EaM is oxidized by 17b-hydroxysteroid dehydrogenases to estromustine (EoM).
EaM and EoM then yield 17b-estradiol and estrone,
respectively, by hydrolysis (Gunnarsson et al, 1984).
Furthermore, 17b-estradiol
is hydroxylated by Cytochrome P450 (CYP) 1A1, 1A2 and 3A4 to yield
2-hydroxyestradiol (Lakhani et al, 2003). 2-hydroxyestardiol can compete with dopamine receptor effectively (Schaeffer et al, 1979). It was
also reported that 2-hydroxyestradiol behaves like an antagonist for dopaminergic receptors in striatum and pituitary (Paden et al, 1982).
The m1 (3801T>C) and intervening sequence (IVS)
1-728 (G>A) are intronic single nucleotide polymorphisms (SNPs), and m2
(2455A>G) is an exonic SNP of the CYP1A1 gene. The minor genotypes of m1 and
m2 polymorphisms have been reported to increase its enzymatic activity (Cosma
et al, 1993; Crofs et al, 1994), and reflect the mass of catechol estrogen
transformation from 17b-estradiol and estrone. Thus, the SNPs of the CYP1A1 gene might play a role in
modulating the metabolism of EMP and act as one of the determining factors for
the inter-individual variations in adverse effects of EMP therapy. To find out
the link between genotypes encoding the enzymes of EMP metabolism and its
adverse effects, we evaluated m1, m2, and IVS1-728 polymorphisms in the CYP1A1
gene among the prostate cancer patients treated with EMP.
A. Study design and treatment plan
A total of 126 patients with untreated advanced prostate cancer were enrolled in this study (Table
1). Age range was 48 to 89 years (mean 72.5 years). Patients with
significant active concurrent medical illness, other malignancy, or
cardiovascular diseases were excluded from this study. The Ethics Committee of the University of Tokyo
approved this study and prior to study written informed consent was obtained
from each patient. The treatment regimens were oral EMP alone (280 mg/day) for
42 patients, oral EMP (280 mg/day) plus luteinizing-hormone releasing-hormone
agonist (LH-RHa) or surgical castration for 13 patients, and oral EMP (140 mg/day) plus LH-RHa for 71
patients. Physical condition of the patients and incidence of the adverse
effects were assessed monthly on the basis of the National Cancer
Institute-Common Toxicity Criteria (Version 2.0, Jan. 30, 1998). According to
their medical reports, 42 of 126 (33.3%) patients suffered from GIT during the
low-dose EMP therapy. Then, we compared the genotypes of SNPs in the CYP1A1
gene among the patients with or without GIT.
B. Genotyping assay
Genotyping was
performed by polymerase
chain reaction (PCR) based-direct sequencing method. Genomic DNA was extracted
from the
peripheral blood lymphocytes by standard method. To use it
in PCR solution, concentration
of genomic DNA was adjusted to 100 ng/mL.
Primers used for DNA amplification are forward 5'-CAG TGA AGA GGT GTA GCC
GCT-3' and reverse 5'-TAG GAG TCT TGT CTC ATG CCT-3' for m1; forward 5'-AGT GGC
ACG CTG AAT TCC A-3' and reverse 5'-CCC CTG ATG GTG CTA TCG AC-3' for m2; forward
5'-TGT TCT CAG GGG AAT TAG GG-3' and reverse 5'-AAG CAA TGT GGT TTG GGA AG-3'
for IVS1-728. Melting temperature were 60¡C for m1 and IVS1-728, 58¡C for m2. Cyclic thermal
conditions were 95¡C for 10 minutes for one cycle; 94¡C for 30 seconds, melting
temperature for each set of primers, for 30 seconds, 72¡C for 3 minutes for 37
cycles; followed by a cycle of 72¡C for 10 minutes. The
amplification reactions of each SNP were performed in 50 mL solution containing 100 ng of genomic DNA, 5 mL of 10xPCR Gold Buffer, 1.5 mmol MgCl2 solution,
0.2 mmol dNTPs, 1.25 U of AmpliTaq Gold DNA polymerase (Applied Biosystems,
Branchburg, NJ, USA), and 0.5 mM of each specific primer
(synthesized by Fasmac, Atsugi, Kanagawa, Japan). GeneAmp PCR
System 9700 (Applied
Biosystems, Foster City, CA, USA) was used to
perform PCR. All
PCR amplicons were purified with the Montage PCRm96
Plate (Millipore Corporation, Bedford, MA, USA) to remove deoxynucleotide
triphosphates and excess primers. All sequencing reactions were performed by
dye terminator chemistry (ABI PRISM BigDye Terminator v3.1 Cycle Sequencing
Kit; Applied Biosystems, Warrington, UK) with each sequencing primer, and the
products were purified with the MultiScreen filter plates (Millipore
Corporation, Bedford, MA, USA) with Sephadex G-50 Superfine (Amersham Biosciences,
Uppsala, Sweden). Purified samples were applied to an ABI Prism 3700 DNA
Analyzer (Applied Biosystems, Foster City, CA, USA), and sites of polymorphisms
were identified with Sequencher software (version 4.1.2; Gene Codes Corporation,
Ann Arbor, MI, USA).
C. Statistical analysis
The allele
frequency of each SNP was estimated by direct count and assessed for deviation
from the Hardy-Weinberg equilibrium by using c2 tests. Univariate and multivariate
analyses were conducted by nominal logistic regression analysis. In the
multivariate analysis, OR, 95% CI and P
value were obtained after adjustment for age, baseline PSA level, performance status, clinical stage, Gleason score and dose of EMP.
EH program (version 1.20) was used for haplotype analyses. These statistical
analyses were conducted by JMP software, version 5.1.2 (SAS, Cary, NC) and the P
value was considered as significant when it was less than 0.05.
Table 1. Patient
characteristics.
|
Characteristics |
Number |
|
Age (mean ± SD) |
72.5 ± 8.8 years |
|
Baseline PSA (mean ± SE) |
418.3 ± 106.7 ng/mL |
|
Performance status |
|
|
0 |
93 |
|
1 |
26 |
|
2 |
7 |
|
Clinical stage |
|
|
C |
60 |
|
D |
66 |
|
Gleason score |
|
|
2 to 7 |
71 |
|
8 to 10 |
55 |
|
Dose of EMP |
|
|
140 mg/day |
71 |
|
280 mg/day |
55 |
SD, standard deviation; SE, standard error; PSA, prostate specific antigen.
Figure 1. Metabolic pathway of estramustine
phosphate (EMP). EMP is dephosphorylated to yield estramustine (EaM). EaM is
oxidized by 17b-hydroxysteroid dehydrogenases (HSD17Bs) to
estromustine (EoM). EaM and EoM then yield 17b-estradiol and estrone, respectively, by
hydrolysis. Furthermore, 17b-estradiol is hydroxylated by
Cytochrome P450 (CYP) 1A1, 1A2 and 3A4 to yield 2-hydroxyestradiol.
Of the 126
patients, 42 (33.3%) suffered from GIT
during low-dose EMP therapy. Seventy-one patients were administered EMP at a dose of 140 mg/day
and 21 (29.6%) of them suffered from
GIT. Fifty-five patients were administered EMP
at a dose of 280 mg/day and 21 (38.2%) of them suffered from GIT. Incidence of GIT was more frequent in the group of EMP
280 mg/day, however, it was not
statistically significant (c2 = 1.03, P =
0.31). Table 2 shows grade and
symptoms of GIT. Approximately 70% of total GIT were grade 1
and the most common GIT was anorexia (45.2%). One patient developed hematemesis
associated with grade 3 gastric ulcer.
We
performed genotyping assay for 3 SNPs in the CYP1A1 gene and frequency of each
genotype is shown in Table
3 and 4. The distribution of
genotypes of these SNPs did not deviate from the Hardy-Weinberg equilibrium. It
was observed that the major allele homozygous genotypes of m1 and IVS1-728 are
frequent among the patients suffered from GIT. The associations between genotypes of m1, m2, and IVS1-728 polymorphisms with
GIT are shown in Table 5. The major alleles
homozygous genotypes of m1 and IVS1-728 polymorphisms are significantly frequent among the patients suffered from GIT.
Univariate analysis shows that the frequency of T/T genotype of m1 and G/G
genotype of IVS1-728 are significantly associated with GIT (T/T genotype of m1, OR 2.78; 95% CI,
1.31 to 6.07; P < 0.01; and G/G genotype of IVS1-728, OR 3.41; 95% CI, 1.59 to 7.56; P < 0.01). Multivariate analysis demonstrated an independent
significant relationship between m1, IVS1-728 polymorphisms and GIT (T/T
genotype of m1, OR2.69; 95% CI, 1.24 to 5.96; P = 0.01; and G/G genotype of IVS1-728, OR 3.31; 95% CI,
1.52 to 7.47; P < 0.01).
Table 2. GIT
observed during EMP therapy (n = 42).
|
GIT grade
of the NCI-CTC |
||||
|
|
Grade 1 |
Grade 2 |
Grade 3 |
Total |
|
|
n (%) |
n (%) |
n (%) |
n (%) |
|
Anorexia |
14 (33.3) |
5 (11.9) |
0 |
19 (45.2) |
|
Heartburn |
11 (26.2) |
3 (7.1) |
0 |
14 (33.3) |
|
Nausea and Vomiting |
5 (11.9) |
3 (7.1) |
0 |
8 (19.0) |
|
Gastric ulcer |
0 |
0 |
1 (2.4) |
1 (2.4) |
|
Total,
n (%) |
30 (71.4) |
11 (26.2) |
1 ( 2.4) |
42 (100) |
GIT,
gastrointestinal toxicity; NCI-CTC, National Cancer Institute-Common Toxicity
Criteria.
Table 3. Allele
frequency of m1, m2, and IVS1-728 polymorphisms with Hardy-Weinberg equilibrium
test.
|
dbSNP ID |
|
rs4646903 |
rs1048943 |
rs4646421 |
|
|
Trivial name |
|
m1 |
m2 |
– |
|
|
Position |
|
3801T>C |
2455A>G |
IVS1-728G>A |
|
|
Allele frequency |
Major allele |
T: 0.66 |
A: 0.79 |
G: 0.66 |
|
|
|
Minor allele |
C: 0.34 |
G: 0.21 |
A: 0.34 |
|
|
HWE |
c2 |
0.44 |
2.05 |
0.61 |
|
|
P value |
|
NS |
NS |
NS |
|
–, not applicable; HWE,
Hardy-Weinberg equilibrium; NS, not significant.
Table 4. Distribution of genotypes in m1, m2, and IVS1-728 loci
with or without GIT.
|
Locus |
|||||||||||
|
m1 |
|
m2 |
|
IVS1-728 |
|
||||||
|
Genotypes |
GIT (+), n=42 |
GIT (–), n=84 |
|
Genotypes |
GIT (+), n=42 |
GIT (–), n=84 |
|
Genotypes |
GIT (+), n=42 |
GIT (–), n=84 |
|
|
C/C |
4( 9.5)* |
12(14.3) |
|
G/G |
1 (2.4) |
7(8.3) |
|
A/A |
4 ( 9.5) |
13(15.5) |
|
|
T/C |
12 (28.6) |
41 (48.8) |
|
A/G |
10 (23.8) |
26 (31.0) |
|
G/A |
11 (26.2) |
42(50.0) |
|
|
T/T |
26 (61.9) |
31 (36.9) |
|
A/A |
31 (73.8) |
51 (60.7) |
|
G/G |
27 (64.3) |
29(34.5) |
|
* No. of patients (%), GIT,
gastrointestinal toxicity; IVS, intervening sequence.
The results of haplotype analyses are shown in Table 6. It is recognized from haplotype analyses that the chance of GIT is over two times higher when ÔAÕ nucleotide in m2 and ÔGÕ nucleotide in IVS1-728 loci are present in a same allele compared with other combinations (OR, 2.33; 95% CI, 1.00 to 5.41; P = 0.05). Furthermore, when the patients represent ÔTÕ nucleotide in m1, ÔAÕ nucleotide in m2 and ÔGÕ nucleotide in IVS1-728 locations in a same allele, the risk of GIT was enhanced approximately 12 times higher than other allelic combinations (m1+m2+IVS1-728 = T+A+G, OR, 11.86; 95% CI, 3.61 to 39.01; P < 0.01).
IV. Discussion
Withdrawal of chemotherapy due to drug toxicities may
allow disease progression and worsen the survival of the patients. Also additional treatments and
measures are required to manage the patients for adverse effects. Therefore,
selection of suitable patients prior to commence the therapy might be
beneficial for survival of patients as well as medical economy.
GIT is one of the major adverse effects of EMP therapy.
About 25.9% patients suffered from GIT during EMP therapy (Kitamura, 2001 and
2002). To overcome this
adverse effect is crucial, however, the mechanism of GIT during EMP therapy is
not well known.
The allele
frequencies of these three polymorphisms are shown in the database of National
Cancer Institute (NCI) (http://snp500cancer.nci.nih.gov/snp.cfm).
Allelic frequencies of m1 and IVS1-728 in our patients are very similar to that
of NCI data. However, minor allelic frequency of m2 among the patients appeared
higher than
Table
5. Relation
between polymorphisms of the CYP1A1 gene and risk of GIT (univariate and
multivariate analyses).
|
Factors |
Univariate
|
|
Multivariate
|
||||
|
|
OR |
95% CI |
P value |
|
OR |
95% CI |
P value |
|
|
|
|
|
|
|
|
|
|
ml |
|
|
|
|
|
|
|
|
T/C & C/C |
1.0* |
|
|
|
1.0* |
|
|
|
T/T |
2.78 |
1.31 to
6.07 |
< 0.01 |
|
2.69 |
1.24 to
5.96 |
0.01 |
|
m2 |
|
|
|
|
|
|
|
|
A/G &G/G |
1.0* |
|
|
|
|
|
|
|
A/A |
1.82 |
0.82 to
4.25 |
NS |
|
1.83 |
0.81 to
4.39 |
NS |
|
IVS1-728 |
|
|
|
|
|
|
|
|
G/A &A/A |
1.0* |
|
|
|
1.0* |
|
|
|
G/G |
3.41 |
1.59 to
7.56 |
< 0.01 |
|
3.314 |
1.52 to
7.47 |
< 0.01 |
|
Age |
|
|
|
|
|
|
|
|
< 73 |
1.0* |
|
|
|
1.0* |
|
|
|
³ 73 |
0.68 |
0.32 to
1.43 |
NS |
|
0.80 |
0.37 to
1.74 |
NS |
|
Baseline PSA level |
|
|
|
|
|
|
|
|
< 418 ng/mL |
1.0* |
|
|
|
1.0* |
|
|
|
² 418 ng/mL |
1.09 |
0.38 to
2.92 |
NS |
|
1.13 |
0.35 to
3.46 |
NS |
|
Peformance status |
|
|
|
|
|
|
|
|
0 and 1 |
1.0* |
|
|
|
1.0* |
|
|
|
2 |
0.32 |
0.02 to
1.94 |
NS |
|
0.25 |
0.01 to
1.69 |
NS |
|
Clinical stage |
|
|
|
|
|
|
|
|
C |
1.0* |
|
|
|
1.0* |
|
|
|
D |
0.87 |
0.41 to
1.82 |
NS |
|
0.71 |
0.30 to
1.64 |
NS |
|
Gleason score |
|
|
|
|
|
|
|
|
2 to 7 |
1.0* |
|
|
|
1.0* |
|
|
|
8 to 10 |
1.27 |
0.60 to
2.69 |
NS |
|
1.35 |
0.59 to
3.09 |
NS |
|
Dose of EMP |
|
|
|
|
|
|
|
|
140 mg/day |
1.0* |
|
|
|
1.0* |
|
|
|
280 mg/day |
1.47 |
0.70 to
3.11 |
NS |
|
1.72 |
0.78 to
3.81 |
NS |
IVS,
intervening sequence; EMP, estramustine phosphate; PSA, prostate-specific
antigen; OR, odds ratio; CI, confidence interval; NS, not
significant.
*Reference
OR, 95%
CI and P value were obtained after adjustment for age, baseline PSA level,
performance status, clinical stage, Gleason score, and dose of EMP.
Table 6. Results of
haplotype analyses between m1, m2, and IVS1-728 polymorphisms.
|
Allelic combination |
Number of patients |
OR (95%
CI) |
P value |
|
|
|
GIT (+) |
GIT
(–) |
|
|
|
m1+m2 =
T+A others |
32.00 10.00 |
50.91 33.09 |
2.08 (0.90 to 4.79) |
NS |
|
m1+IVS1-728
= T+G |
32.00 |
50.00 |
|
|
|
others |
10.00 |
34.00 |
2.18 (0.95 to 5.01) |
NS |
|
m2+IVS1-728
= A+G |
32.50 |
50.00 |
|
|
|
others |
9.50 |
34.00 |
2.33 (1.00 to 5.41) |
0.05 |
|
m1+m2+IVS1-728
= T+A+G |
38.62 |
41.18 |
|
|
|
others |
3.39 |
42.82 |
11.86 (3.61 to 39.02) |
< 0.01 |
IVS, intervening sequence; GIT,
gastrointestinal toxicity; OR, odds ratio; CI, confidence interval;
NS, not significant.
that of
NCI data (our data, A: G = 0.79: 0.21; NCI data, A: G=0.88: 0.12). Perhaps this
variation is due to racial differences and the factors related to the disease.
Further studies are needed to clarify the cause of this variation.
Our data demonstrated an association between genetic polymorphisms of m1, m2 and IVS1-728 in
the CYP1A1 gene and GIT during the EMP therapy. Therefore, genotyping of these
polymorphisms prior to EMP therapy will be useful to estimate the risk of GIT. At the present,
we could not compare the serum 2-hydroxyestradiol levels on the basis of
genotypes. However, the mechanisms of emesis and comparative
study of serum 2-hydroxyestradiol levels in different genotypes of these three
SNPs during EMP therapy are remaining for future study. Our results are novel
and the association was statistically significant, however, much larger
population is needed to confirm our data. Because, in the haplotype analyses,
one allelic subgroup had less than five subjects.
From the results reported herein, genotyping of these
three SNPs could be a useful tool to find out the risk group of patients for
GIT prior to commence the EMP therapy in prostate cancer. Finally, using a tailor-made medication by detecting
the risk group, the drug compliance of EMP could be increased markedly.
Acknowledgements
We would like to give special thanks to A. Hirose and
E. Tanaka for their excellent technical assistance. This study was supported by
a Grant-in-aid from the Japanese Ministry of Education, Science, Sports and
Culture (Project No. 15390485) and a grant from Yamaguchi Endocrine Research
Association.
Cosma G, Crofts F, Taioli E, Toniolo P, and Garte S (1993) Relatationship between genotype
and function of the human CYP1A1 gene. J
Toxicol Envion Health 40, 309-316.
Crofts F, Taioli E, Trachman J, Cosma GN, Currie D, Toniolo P, and Garte
SJ (1994) Functional significance of
different human CYP1A1 genotypes. Carcinogenesis
15, 2961-2963.
Gunnarsson PO and Forshell GP (1984)
Clinical pharmacokinetics of estramustine phosphate. Urology 23, 22-27.
Kitamura T (2001) Necessity
of reevaluation of estramustine phosphate sodium (EMP) as a treatment option
for first line monotherapy in advanced prostate cancer. Int J Urol 8, 33-36.
Kitamura T, Nishimatsu
H, Hamamoto T, Tomita K, Takeuchi T, Ohta N (2002) EMP combination chemotherapy and low-dose monotherapy in
advanced prostate cancer. Expert Rev
Anticancer Ther 2, 59-71.
Lakhani NJ, Venitz J, Figg WD, and Sparreboom A (2003) Pharmacogenetics of estrogen metabolism and transport in
relation to cancer. Curr Drug Metab
4, 505-513.
Oudard S, Banu E, Beuzeboc P, Voog E, Dourthe LM, Hardy-Bessard AC,
Linassier C, Scotte F, Banu A, Coscas Y, Guinet F, Poupon MF, and Andrieu JM (2005) Multicenter randomized phase II
study of two schedules of docetaxel, estramustine, and prednisone versus
mitoxantrone plus prednisone in patients with metastatic hormone-refractory
prostate cancer. J Clin Oncol 23,
3343-3351.
Paden CM, McEwen BS, Fishman J, Snyder L, and DeGroff V (1982) Competition by estrogens for
catecholamine receptor binding in vitro.
J Neurochem 39, 512-520.
Schaeffer JM and Hsueh AJW (1979)
2-Hydroxyestradiol interactions with dopamine receptor binding in rat anterior
pituitary. J Biol Chem 254,
5606-5608.
Vaishampayan U, Fontana J, Du W, and
Hussain M (2002) An active regimen
of weekly paclitaxel and estramustine in metastatic androgen-independent
prostate cancer. Urology 60, 1050-1054.
