Intracavitary chemotherapy with activated cyclophosphamides and simultaneous systemic detoxification with protector thiols in Sarcoma 180 ascites tumor.
Activated cyclophosphamides such as 4-sulfoethylthiocyclophosphamide (mafosfamide) are suitable for a local intracavitary chemotherapy, whereas cyclophosphamide requires a metabolic activation. Mafosfamide administered i.p. in mice was less toxic (50% lethal dose, 640 mg/kg) than its i.v. application (50% lethal dose, 480 mg/kg). A further remarkable reduction of toxicity with an increase of the 50% lethal dose of mafosfamide to 1500 mg/kg was obtained by the simultaneous i.v. application of the protector thiol cysteine (mafosfamide:cysteine ratio, 1:5 on molar weight basis). In comparison with the i.v. injection of mafosfamide, the local i.p. application resulted in a 20 times higher concentration versus time product of peritoneal drug levels. The molar ratio of sulfhydryl groups to activated cyclophosphamide (resorbed from the peritoneal cavity) remained high in blood. Therapy studies on Sarcoma 180 ascites tumor of mice revealed that the coadministration of cysteine i.v. in mafosfamide i.p. treatment is superior to mafosfamide i.p. application alone. On the contrary, the simultaneous i.p. application of cysteine is accompanied by a loss of antitumor efficacy. The regimen of local i.p. chemotherapy with activated cyclophosphamide and simultaneous systemic detoxification by an appropriate thiol allows the reduction of the systemic toxicity of treatment without influence on the cancerotoxic activity at the site of local injection and the exposing of the intraabdominal tumor to a much higher concentration of the cytostatic agent.
Wagner
T
T
Mittendorff
F
F
Walter
E
E
D000818:Animals; D001682:Biological Availability; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D003545:Cysteine / Q000008:administration & dosage*; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007700:Kinetics; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy*
C048341:mafosfamide; D003520:Cyclophosphamide; D003545:Cysteine