Correlation between the sensitivity of tumors to treatment with CZ48 and local concentrations of the active metabolite CPT within the tumors.

Crystalline camptothecin-20-O-propionate hydrate (CZ48) is an esterification product from the reaction of natural camptothecin with propionic anhydride. CZ48 has been tested against 29 human tumor lines grown in nude mice as xenografts. Of the tested tumor lines, 28 were found to be responsive to CZ48, by regression or significant inhibition. The total response rate was 97%. However, the effective dose required to achieve the positive response varied from 100 to 2000 mg/kg/day depending on the tumor type. Thus, the sensitivity of tumors to CZ48 treatment varied from tumor to tumor. The most sensitive CLO-breast carcinoma achieved regression when treated with 100 mg/kg/day, while PC3-prostate carcinoma required as high as 1000 mg/kg/day to achieve a definitive response. To determine the reason for these differences in sensitivities among the tumors, we treated 9 human xenografts grown in nude mice with 1000 mg/kg/day CZ48 until saturation and measured the local concentrations of the parental CZ48 as well as the corresponding metabolite camptothecin (CPT) in the tumors with the established high-performance liquid chromatography procedure. Results showed that the sensitivities of these tumors to CZ48 treatment were not affected by local concentrations of the active metabolite CPT in the tumors, but instead by the types of tumors.