The effect of "antiangiogenesis"
therapy using
cortisone acetate (CA) with or without
heparin on
tumor growth as well as in combination with
chemotherapy was investigated. C3H mice were implanted intradermally with N-[4-(5-nitro-2-furyl)-thiazolyl]
formamide induced undifferentiated
transitional cell carcinoma, MBT-2, in the right flank. The treatment was initiated 9 to 10 days after
tumor inoculation. Daily
injections of CA (250 mg/kg s.c.) suppressed
tumor growth significantly in a dose dependent fashion. Administration of
heparin (Elkins-Sinn) at the concentration of 200, 400, or 1000 units/ml in
drinking water for 3 to 6 days was neither additive nor detrimental to the effect of CA.
Chemotherapy was combined with CA; 3 days of administration of 250 mg/kg of CA in tapering doses was used. The chemotherapeutic agent was injected once 24 h before the initial CA. Combinations of
chemotherapy (
Adriamycin, 2.5-7.5 mg/kg i.v;
cisplatin, 3-9 mg/kg i.p.;
cyclophosphamide, 50-150 mg/kg i.p.; cis-(diammino)(1,1-cyclobutanedicarboxylate)
platinum(II) (
JM-8), 60-150 mg/kg i.p.;
mitomycin C, 3-4.5 mg/kg i.p.) with CA showed additive suppression of
tumor growth. Mice tolerated
chemotherapy alone, CA alone, and both in combination. CA combined with
JM-8 was not tolerated. Mice tolerated 100 to 150 mg/kg of
JM-8, whereas the addition of CA to
JM-8 resulted in a 66% (6 of 9) to 89% (8 of 9) mortality rate. CA at a concentration of 5 and 25 micrograms/ml showed no direct cytotoxic activity against MBT-2 cells in vitro. However, 3 days of administration of 250 mg/kg of CA inhibited
tumor angiogenesis generated by MBT-2 cells in C3H mice using a dorsal air sac assay. The data suggest that CA alone inhibits
tumor angiogenesis in C3H mice and that antiangiogenesis
therapy enhances the antitumor efficacy of chemotherapeutic agents without increasing host toxicity (except for
JM-8).