POTENT AND BROAD ANTITUMOR EFFECTS OF DX-8951F, A WATER-SOLUBLE CAMPTOTHECIN DERIVATIVE, AGAINST VARIOUS HUMAN TUMORS XENOGRAFTED IN NUDE-MICE

Purpose: We have previously reported that DX-8951f, a water-soluble an d nonprodrug camptothecin (CPT) derivative, exhibits both high in vitr o potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The purpose of this study was to evaluate the therapeutic efficacy of DX-8951f against human tumor xenografts in nude mice and to compare its activity with those of CPT-11 and other current CPT derivatives.,Methods: The antitumor activity of DX-8951f a gainst xenografts of several different types of human tumors was deter mined in nude mice using a schedule in which DX-8951f was administered intravenously every 4th day for a total of four injections. Results: Against both gastric adenocarcinoma SC-6 and its CPT-11-resistant vari ant, SC-6/CPT-11, DX-8951f demonstrated superior antitumor activity an d antitumor activity over a broader range of doses than did CPT-11, SK &F104864 (hycamtin, topotecan) and GG-211 (GI147211). DX-8951f at 75 m g/kg was effective (growth inhibition rate IR greater than or equal to 58%) against 15 of 16 lines of human cancers examined (6 colon cancer s, 5 lung cancers, 2 breast cancers, 1 renal cancer and the above 2 ga stric cancers), and exhibited excellent antitumor activity (IR greater than or equal to 80%) against 14 of these lines. CPT-11 exhibited ant itumor activity with IR values of 58% and higher against Il lines and IR values of 80% and higher against only eight of the same 16 human tu mors. DX-8951f was effective in inhibiting the growth of an SN-38-resi stant tumor and some P-glycoprotein-expressing tumors, but CPT-11 was not. Conclusions: DX-8951f exhibited potent antitumor activity against various types of human tumor xenografts. Its in vivo antitumor effect s were superior to those of current camptothecin analogs against certa in tumors.