IV. Discussion
The results presented in this paper show that
methylglyoxal in combination with ascorbic acid could deliver significant
beneficial effects to a group of cancer patients. Total forty-six patients were
included in the study and these patients were suffering from different types of
cancer. The study period for the patients was 4 to 56 months. The remarkable
finding of this drug regimen is that it is effective against a wide variety of
cancer. This is in sharp contrast to other anticancer drugs now widely used.
This remarkable effect of methylglyoxal over a wide range of cancer type
suggests that all the different types of cancer may have common altered site(s)
and which is targeted by methylglyoxal. In fact as mentioned before previous in vitro studies in our laboratory with
animal and human tissue materials had suggested that the glycolytic enzyme
glyceraldehyde-3-phosphate dehydrogenase and mitochondrial complex I might be
specifically altered in malignant cells (Halder et al, 1993; Ray et al,
1994, 1997a, b; Biswas et al, 1997).
As mentioned in the Introduction
that despite the documented anticancer property of methylglyoxal it had not
been tested till recently for treating cancer patients. On the other hand,
methylglyoxal bisguanylhydrazone, a derivative of methylglyoxal had been used
to treat human medulloblastoma xenografts in nude mice with no success
(Friedman et al, 1986). This
compound when tested to treat to cancer patients had been found to be toxic and
with little beneficial effect to the host (Gastaut et al, 1987).
This apathy of using methylglyoxal possibly stems from
the widespread belief that, methylglyoxal is toxic. Recently, numerous papers
have appeared in the literature, which mostly with in vitro studies under non-physiological conditions have shown that
methylglyoxal reacts with arginine, lysine and free terminal amino groups in
proteins resulting in AGE (advanced glycation end products) formation. The
possibilities of many deleterious effects of methylglyoxal in the body have
been extrapolated based mostly on these in vitro studies. The notable
complications are related to diabetes, hypertension and cataract formation (Lee
et al, 1999; Morgan et al, 2002; Bourajjaj et al, 2003; Kumar et al, 2004). Evidences have also
been put forward that methylglyoxal is mutagenic (Murata- Kamiya et al, 2000) and induces reactive
oxygen species formation (Chang et al,
2005).
On the other hand as mentioned before several in vivo and in vitro studies suggest that methylglyoxal may have some
beneficial effects too particularly to higher animals. It inhibits
mitochondrial respiration and glycolysis of malignant cells, whereas these
functions of normal cells are unaffected (Halder et al, 1993; Ray et al,
1994, 1997a,b; Biswas et al, 1997;
Ray and Ray, 1998). There is a report that methylglyoxal rapidly suppresses the
mitochondrial permeability transition thereby preventing from the possible
deleterious effect of high Ca2+ and ganglioside (Speer et al, 2003). Methylglyoxal can also
protect gastric mucosa against different necrotizing agents (Al-Shabanah et al, 2000).
The most remarkable beneficial effect of methylglyoxal
had originated from the in vivo studies by Szent Gyrgyi and colleagues
and Apple and Greenberg, which showed the curative effect of methylglyoxal on
cancer-bearing animals (Apple and Greenberg, 1967; Apple and Greenberg, 1968;
Egyd and Szent-Gyrgyi, 1968; Conroy, 1979). From the results of all these
studies it is logical to conceive that many of the purported in vitro toxic
effects of methylglyoxal may be counteracted by many countervailing reactions
in intact living animals. Our previous investigation on the possible toxic
effect of methylglyoxal supports this conjecture. Pharmacokinetic studies had
indicated that methylglyoxal is appropriately cleared from the body (Ghosh et al, 2006).
The apparent lack of toxicity of methylglyoxal-based
treatment and also the wide applicability deserve that it should be further
studied. Because methylglyoxal is a normal metabolite, the presence of several
active catabolyzing enzymes such as glyoxalase I may diminish its efficacy (Ray
and Ray, 1998; Ghosh et al, 2006;
Cooper, 1984). There are several synthetic inhibitors of glyoxalase I
(Creighton et al, 2003). By in-vivo experiments it should at
first be ascertained whether these compounds are non-toxic and effective in
augmenting the anticancer effect of methylglyoxal. Then some of these compounds
in combination with methylglyoxal could be used to treat cancer patients.
Mode of treatment should be another consideration. It is expected that intravenous and/or peritumoural injection may significantly improve the efficacy. Similar to all form of cancer treatment early diagnosis is advantageous. Because methylglyoxal acts specifically against malignant cells it has the potential to destroy metastasis also. But if vital organ(s) are irreversibly damaged then it is very difficult to bring back the patients to normalcy.
At present combination chemotherapy is widely used in
the treatment of cancer. Recently besides our work a paper has appeared
describing a study of treatment of non-Hodgkin lymphoma by two different
combinations of drugs, one of which contained methylglyoxal. However, the drug
combination, which contained methylglyoxal showed no better results (Chamorey et al, 2005). In our present work, we
show that only methylglyoxal in combination with ascorbic acid is quite
effective in arresting tumour growth and in some cases could completely
eliminate the malignant tissues. Previous in vitro study from our laboratory with human tissue materials
had shown that the anticancer effect of methylglyoxal was significantly
augmented in presence of ascorbic acid (Ray et al, 1991).
Finally, our next task will be to further evaluate the
efficacy of methylglyoxal and ascorbic acid treatment using a large number of
patients and different types of cancers at different stages of the disease. If
found effective then to further improve the treatment.
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