Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice.
OBJECTIVE
We have previously reported that DX-8951f, a water-soluble and nonprodrug camptothecin (CPT) derivative, exhibits both high in vitro 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 against xenografts of several different types of human tumors was determined 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 variant, SC-6/CPT-11, DX-8951f demonstrated superior antitumor activity and antitumor activity over a broader range of doses than did CPT-11, SK&F104864 (hycamtin, topotecan) and GG-211 (GI147211). DX-8951f at 75 mg/kg was effective (growth inhibition rate IR > or = 58%) against 15 of 16 lines of human cancers examined (6 colon cancers, 5 lung cancers, 2 breast cancers, 1 renal cancer and the above 2 gastric cancers), and exhibited excellent antitumor activity (IR > or = 80%) against 14 of these lines. CPT-11 exhibited antitumor activity with IR values of 58% and higher against 11 lines and IR values of 80% and higher against only eight of the same 16 human tumors. DX-8951f was effective in inhibiting the growth of an SN-38-resistant 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 effects were superior to those of current camptothecin analogs against certain tumors.
New Product Research Laboratories IV, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
E
E
Kumazawa
T
T
Jimbo
Y
Y
Ochi
A
A
Tohgo
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D000077146:Irinotecan; D007680:Kidney Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D013274:Stomach Neoplasms / Q000188:drug therapy; D013370:Subrenal Capsule Assay; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; C095887:exatecan; D002166:Camptothecin