The experimental antitumor agents Phortress and doxorubicin are equiactive against human-derived breast carcinoma xenograft models

Abstract

Phortress (the dihydrochloride salt of the lysylamide prodrug of 2-(4-amino-3-methylphenyl)-5-fluoro-benzothiazole (5F 203)) is an experimental antitumor agent with potent and selective activity against human-derived carcinomas of breast, ovarian and renal origin. UK clinical trials of Phortress are scheduled to begin in 2004. The mechanism of action of Phortress is distinct from all classes of chemotherapeutic agents currently in the clinic, and involves metabolic activation by cytochrome P450 (CYP) 1A1 to electrophilic species, which generate DNA adducts in sensitive tumors only. In the present study, the antitumor efficacy of Phortress has been compared with that of doxorubicin (Dox) in nine human-derived mammary carcinoma xenograft models, cultivated subcutaneously in the flanks of nude mice. In addition, cyp1a1 mRNA expression was measured in tumors of control and treated animals. Phortress compared favorably with Dox: significant activity, independent of estrogen receptor (ER) status, was established in 7/9 xenografts; in one xenograft model, Phortress elicited superior antitumor activity; no model demonstrated complete resistance to Phortress. In accordance with this observation, all xenografts available for examination (8) displayed clear induction of cyp1a1 expression upon treatment of mice with Phortress whereas Dox failed to induce cyp1a1 expression in all models. Prolonged viability of tumor fragments, recovered for treatment ex vivo could not be sustained; thus correlations between tumor cells' response to Phortress and cyp1a1 or cyp1b1 inducibility following 5F 203 treatment could not be determined with confidence.