Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics.
Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose-response curves were interpolated to provide 50% lethal concentrations (LC(50)). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC(50) value (0.26+/-0.06 microg ml(-1); P=0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.
Rational Therapeutics, Inc., 750 East 29th Street, Long Beach, CA 90806, USA. robert.nagourney@rationaltherapeutics.com
R A
RA
Nagourney
B L
BL
Sommers
S M
SM
Harper
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S
Radecki
S S
SS
Evans
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D007928:Lethal Dose 50; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin