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| |  DG DISPATCH - NCI-EORTC-AACR: Research Suggests Way To Make Camptothecin More Tolerable For Patients By Ed Susman Special to DG News
AMSTERDAM, THE NETHERLANDS -- November 10, 2000 -- Forty years ago researchers looked at the drug camptothecin as an anticancer agent, but the drug was put aside because it was too toxic for patients. Now researchers at the Institute for Drug Development, San Antonio, Texas, have dusted off camptothecin and have attached it to another molecule, polyethylene glycol (PEG), to make the whole substance more water soluble. Desiree Ho, MD, a clinical research fellow at the University of Texas-affiliated institute, said the attachment to the PEG makes camptothecin better tolerated by patients. "Camptothecin is an active prototypical topoisomerase I inhibitor," said Hao at the 11th annual National Cancer Institute-European Organization for Research and Treatment of Cancer-American Association for Cancer Research symposium (NCI-EORTC-AACR) symposium on new drugs in cancer therapy, being held this week in Amsterdam, The Netherlands. She said that conjugation of camptothecin to chemically-modified PEG at a specific position on the molecule confers water-solubility. She said it also decreases protein binding and enhances the potential of tumor targeting because the combination increases vascular permeation. Dr. Hao explained that when the drug was tested in a pre-clinical setting, the PEG-camptothecin exhibited broad-spectrum antitumor activity, a favorable pharmacologic profile and superior antitumor activity in comparison to other currently approved topoisomerase inhibitors. Even in the Phase I study to test the toxicity of the combination, Dr. Hao reported, it appears to have biological activity against small cell lung cancer and against an occult primary tumor. One patient with non-small cell lung cancer has had stable disease through five cycles of treatment. Of the 16 patients in the study, 11 are men; the average age of the cohort is 58. In addition to studying tolerability and pharmacokinetics, Dr. Hao is also performing dose-ranging studies, having been able to escalate dosages from 600 mg to 5,600 mg. At the higher dosages, she has observed Grade 4 neutropenia in three patients, Grade 4 thrombocytopenia in a single patient and readily-resolvable Grade 3 hematuria in two patients. One patient reported a Grade 3 hypersensitivity reaction but that patient was rechallenged successfully. However, Hao said she doesn’t believe that the maximum tolerated dose of the PEG-camptothecin molecule has been reached. Some of her patients have endured 15 cycles of treatment-an intravenous infusion for one hour every three weeks-without experiencing treatment limiting side effects. "That’s pretty good," Dr. Hao said. She treated 16 patients in the Phase I study that is continuing.
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