A NEW WATER-SOLUBLE CAMPTOTHECIN DERIVATIVE, DX-8951F, EXHIBITS POTENT ANTITUMOR-ACTIVITY AGAINST HUMAN TUMORS IN-VITRO AND IN-VIVO

CPT-11, a semisynthetic derivative of camptothecin, exhibited strong a ntitumor activity against lymphoma, lung cancer, colorectal cancer, ga stric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-dru g that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro- drug analog of camptothecin, DX-8951f. It showed both high in vitro po tency against a series of 32 malignant cell lines and significant topo isomerase I inhibition. The anti-proliferative activity of DX-8951f, a s indicated by the mean GI(50) value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These t hree derivatives of camptothecin showed similar patterns of differenti al response among 32 cell lines, that is, their spectra of in vitro cy totoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastri c adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK &F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug r esistance. These data suggest that DX-8951f has a high antitumor activ ity and is a potential therapeutic agent.