As I noted in a previous post on arsenic trioxide, you just never know what source will give rise to the next promising drug. Last week's New England Journal of Medicine marked a key study on an old drug, mitotane (Lysodren, Bristol-Myers Squibb), that is a structural derivative of the pesticide, DDT.
Adrenocortical carcinoma is a rare cancer with only 16-38% of patients surviving for five years. Following surgical resection, 75-85% of patients experience a relapse. Therefore, a group of Italian and German researchers sought to identify drugs that could be used as adjunct therapy in this population of patients.
The unique aspect of adrenocortical carcinoma is that, like normal adrenal glandular tissue, it contains enzymes of the cytochrome P450 class that normally act as steroid hydroxylases in the synthesis of adrenal steroids. It just so happens that these same enzymes also bioactivate mitotane into a chemically-reactive DNA damaging agent. Hence, in pharmacology terms mitotane is referred to as a "prodrug": an agent that is inactive by itself but requires metabolic activation to exert its biological effect.
Mitotane (also known as o,p'-DDD, or more formally as 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl) ethane) is therefore only effective against cancers that have such enzymes (specifically CYP11B1). So, while this new report is quite exciting the results probably only hold promise for those patients with rare adrenocortical carcinoma.
Here are the salient points from the abstract:
Baseline features in the mitotane group and the control group from Italy were similar; the German patients were significantly older (P=0.03) and had more stage I or II adrenocortical carcinomas (P=0.02) than did patients in the mitotane group. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two control groups (median recurrence-free survival, 42 months, as compared with 10 months in control group 1 and 25 months in control group 2). Hazard ratios for recurrence were 2.91 (95% confidence interval [CI], 1.77 to 4.78; P<0.001) and 1.97 (95% CI, 1.21 to 3.20; P=0.005), respectively. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mainly of grade 1 or 2, but temporary dose reduction was needed in 13% of patients.
These are pretty impressive improvements in survival compared to what we've seen lately with far more expensive targeted biological therapies. However, as I said, the drug will only be useful for a very small subset of cancer patients.
But just as thalidomide and its derivatives have come back to be potentially useful cancer therapies, it should be no surprise that a derivative of DDT might find a place in cancer chemotherapy.
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Question: what is the putative mechanism for differential effect against neoplastic vs. non-neoplastic Cytochrome P450-CYP11B1 using cells?
Regarding the difference in metabolism, this is discussed in Schteingart's accompanying editorial (Schteingart, D. E. (2007). Adjuvant Mitotane Therapy of Adrenal Cancer -- Use and Controversy. NEJM 356: 2415-2418 ) "... the pathway of mitotane metabolism follows the well-known process by which chloramphenicol causes toxicity. Mitotane is hydroxylated at the beta-carbon and quickly transformed by dehydrochlorination into an acyl chloride. The acyl chloride either covalently binds to bionucleophiles in the target cells or through loss of water is transformed into an acetic acid derivative for renal excretion. The initial hydroxylation step is carried out in the mitochondria and catalyzed by a P-450 enzyme, giving adrenal selectivity to the action of mitotane. Developing cancer cells will vary in their ability to metabolize mitotane because of alterations in this metabolic process. Tumors with an ability to metabolize mitotane respond, but those that are unable to metabolize the drug may not. Pineiro-Sanchez et al. published a tritium-release assay to test the ability of tumors to metabolize mitotane. Testing tumors before treatment might help select those with the highest probability of response. "