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758
ANTICANCER ACTIVITY OF DX-8951f, A WATER SOLUBLE CAMPTOTHECIN ANALOG, AGAINST HUMAN TUMOR SPECIMENS TAKEN DIRECTLY FROM ADULT AND PEDIATRIC PATIENTS.
K. Davidson, E. Izbicka, R. Lawrence, C. Cerna, L. Gomez, G.M. Clark, R.L. DeJaeger, S. Weitman, D.D. Von Hoff. Institute for Drug Development, San Antonio, TX, The University of Texas Health Science Center at San Antonio, San Antonio, TX, and Daiichi Pharmaceutical Corporation, Fort Lee, NJ.
Current topoisomerase I inhibitors like CPT-11 demonstrate dramatic activity against many adult and pediatric tumors. DX-8951f, a water soluble derivative of camptothecin, has shown activity against malignant cell lines and human tumor xenografts. These studies suggest that the anticancer activity of DX-8951f is greater than that of topotecan. In addition, preliminary studies also suggest that the anti-tumor activity is not MDR-modulated. We have examined the activity of DX-8951f and topotecan in a human tumor-colony forming assay against 47 evaluable specimens taken directly from adult patients and against 7 specimens from pediatric patients. DX-8951f had definite cytotoxic activity in a concentration dependent manner with both 1 hour and continuous exposures against adult specimens representing a broad spectrum of tumors. DX8951f was most effective against non-small cell lung, head and neck, and liver tumors at a 1 hour exposure. In a continuous exposure, DX-8951f was most effective against colon, head and neck, non-small cell lung, ovarian, and prostate tumors. In head to head comparisons of DX-8951f versus topotecan using a 1 hour exposure, DX-8951f was significantly more effective than topotecan at 0.1 and 1.0  g/ml. In pediatric specimens, DX-8951f showed a definite concentration-response effect against kidney, neuroblastoma, and germ cell tumors. In conclusion, DX-8951f is a promising new antineoplastic agent with significant activity against tumors taken directly from patients. This agent is currently in Phase I evaluation in adults with refractory tumors and may represent an advantage over other topoisomerase I inhibitors.
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