12A-870326
台灣(發明)205511已獲證、歐盟990661已獲證、美國6043367已獲證
A glucuronide prodrug of 9-aminocamptothecin was invented that displays high water solubility, low toxicity and good stability. This prodrug is activated by beta-glucuronidase. It displays potent antitumor activity against human tumors in nude mice. It can also be selectively activated at tumor cells after injection of an antibody-glucuronidase conjugate that binds to tumor-associated antigens. This type of treatment can cure solid human xenografts in nude mice.
Camptothecin diplays potent antitumor activity but in very water insoluble. Currently, two water-soluble derivatives of camptothecin have been approved for use in humans. These are CPT-11 and topotecan. Our prodrug displays excellent water solubility and low toxicity. It can be converted to 9-aminocamptothcin by beta-glucuronidase present at the tumor site. Tumor selectivity is thereby achieved. It has demonstrated as good as well as much better activity than CPT-11 against human tumor xenografts. This prodrug may therefore be superior to current drugs in clinical use. In addition, the new prodrug can be employed for antibody-directed enzyme prodrug therapy of cancer. An immunoenzyme composed of a targeting antibody and beta glucuronidase is first injected. This allows accumulation of enzyme at the tumor. The glucuronide prodrug is then injected whereby it is selectively converted to 9-aminocamptothecin at the tumor cells. Selectivity of cancer therapy can be greatly enhanced by this strategy, reducing side-effects of therapy. ●formulation improved (water soluble) ●low toxicity ●tumor selective ●potent antitumor activity
Therapy of human cancers by monotherapy (injection of the glucuronide prodrug alone) or by ADEPT (injection of an antibody-glucuronidase conjugate followed by injection of the prodrug).
羅傅倫、陳基旺、呂玉玲
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前活性的抗腫瘤化合物
