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.