asta-z-7557 and Urinary-Bladder-Neoplasms

The influence of L-cystein on the toxic and therapeutic responses of 4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated" cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein. Simultaneous application of double molar amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic activity is not affected by this ratio of L-cystein so that the protector thiol increases the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity in nude mice and the therapeutic efficacy against the human xenograft. The perfusion experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing limb is only tolerated in combination with L-cystein.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Cyclophosphamide; Cysteine; Female; Humans; Lethal Dose 50; Male; Mice; Mice, Nude; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Sarcoma, Yoshida; Structure-Activity Relationship; Transplantation, Heterologous; Urinary Bladder Neoplasms