Regulation of esterase activity by androgens, both in the liver and in the serum, has been previously demonstrated in a variety of species including mouse, rat, dog and human. Isoenzymes affected include acetylcholinesterase, carboxylesterases and arginine esterases, to name but a few. Liver and serum esterase activity is integral to the activity of 9-nitrocamptothecin 20(S) propionate (CZ112), which is a promising new anticancer agent. These enzymes are responsible for cleaving the propionate side-chain to produce 9-nitrocamptothecin (9NC), the active form of the drug. In working with CZ112, we have found that its toxicity exhibits striking differences between male and female animals. When CZ112 was administered at 20 mg/kg/day in a 5 days on/2 days off treatment regimen to a group of male Swiss NIH nude mice (n=5), only 60% survived the 3 month treatment and even the survivors showed significant signs of toxicity (weight loss, diarrhea). In contrast, female nude mice under the same treatment regimen (n=5) had 100% survival rate and no signs of toxicity. Castrated nude male mice (n=7) treated similarly had an 88% survival rate and exhibited little to no toxicity. Castrated animals, chronically treated with subcutaneous testosterone (n=8) behaved much like intact males: 25% survival + toxicity. Since CZ112 is a prodrug requiring esterase activity to become active, we propose that the higher levels of esterase activity in the intact male animals results in higher serum levels of 9NC become available and toxicity becomes apparent at lower doses.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]