The effect of combretastatin A-4 disodium phosphate in a C3H mouse mammary carcinoma and a variety of murine spontaneous tumors

Purpose: To investigate the activity of combretastatin A-4 disodium phosphate in a transplanted C3H mouse mammary carcinoma and several murine spontaneous tumors. Methods and Materials: The C3H mammary carcinoma was grown in the right rear foot of female CDF1 mice and treated when 200 mm(3) in size. Spontaneous tumors (341-1437 mm(3) in size) arose at different sites in female CDF1 mice that, 19-21 months earlier, had been irradiated. Oxygen partial pressure (pO(2)) distributions in the C3H tumors were measured with an Eppendorf oxygen electrode at various times after injecting combretastatin (100 mg/kg, i.p.) in restrained, nonanesthetized mice. Immediately after measurement, tumors were excised and necrotic fraction determined from histological sections. In the spontaneous tumors, pO(2) was measured before and 3 h after giving combretastatin. The location of these spontaneous tumors required that measurements be made in anesthetised animals, achieved by injecting a mixture of hypnorm and diazepam. Results: In untreated C3H tumors, the mean (+/- 1 SE) percentage of pO(2) values less than or equal to 2.5 mmHg was 32% (+/- 11). This was significantly (Student's t-test; p < 0.05) increased to 74% (+/- 4) within 1 h after injecting combretastatin, and remained at this level for at least 6 h, although some recovery was seen at 12 and 24 h. The necrotic fraction in control tumors was 1.9% (+/- 0.4) and this was significantly increased to 16.1% (+/- 3.7) 24 h after drug administration. In spontaneous tumors, the pO(2) measurements indicated that 5 of 6 showed some response to combretastatin, although the degree of change was variable. Conclusions: Combretastatin increased tumor hypoxia land necrosis in the C3H mammary carcinoma, consistent with the induction of vascular damage. Drug-induced changes in pO(2) were also found in spontaneous: tumors, suggesting that the activity of this drug is not restricted to transplanted tumors alone. (C) 1998 Elsevier Science Inc.