Potentiation of cytotoxicity of zinostatin under acidic conditions in vitro and in vivo.
The cytotoxicity and antitumor effects of zinostatin (NCS) were examined under various conditions of pH using cultured HeLa cells and a transplantable tumor line of WKA rats. The cytotoxicity of NCS against HeLa cells was highly dependent on the pH at ranges of 6-8. When HeLa cells were treated with 0.075 microgram/ml of NCS, the survival rate was about 1% at pH 6.0, while it was near 90% at pH 7.4 and pH 8.0. Even at pH 6.5-6.75, the survival rate was about 50% lower than that seen with pH 7.4 and pH 8.0. The ratio of the dose of NCS for a 90% cell mortality at pH 6.0 to that at pH 7.4 was less than one-seventh. Antitumor effects were assessed by local intra-arterial infusion against tumors 4 or 9 days after inoculation of 10(6) RBT-1 tumor cells into the thigh of rats. When NCS (0.7 mg/kg) in phosphate-buffered saline (PBS) (pH 7.4) or 5 mM lactate (about pH 3.0) was administered, the ratio of average tumor weight about 2 weeks after treatment (tumor weight of the rats given NCS in PBS/tumor weight of the rats given NCS in lactate) was 3.2 or 1.7 for the rats treated 4 or 9 days after tumor inoculation, respectively. Lactate or PBS alone had no effect on the growth of tumor. After treatment there was no difference in body weight change between the group treated with NCS in lactate and the group treated with NCS in PBS. We conclude that the cytotoxicity of NCS was potentiated under acidic conditions, both in vitro and in vivo.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy; D009353:Zinostatin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D009353:Zinostatin