The influence of the protector thiol L-cystein on the toxic and therapeutic responses of stabilized "activated" cyclophosphamide (4-(S-ethanol)-sulfido-cyclophosphamide).
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.
D000818:Animals; D010478:Chemotherapy, Cancer, Regional Perfusion; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D003545:Cysteine; D005260:Female; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D011919:Rats, Inbred Strains; D012517:Sarcoma, Yoshida / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
C037933:Asta Z 7557; D003520:Cyclophosphamide; D003545:Cysteine