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.
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).
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
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