Stoppage of blood flow in 3-methylcholanthrene-induced autochthonous primary tumor due to a novel combretastatin A-4 derivative, AC7700, and its antitumor effect

Abstract

Background: Using several transplanted tumors in rats and mice, we have recently shown that the acute extensive necrosis of tumor nodules is caused by the systemic administration of AC7700, a novel combretastatin A-4 derivative, and that the necrosis can be attributed to irreversible stoppage of tumor blood flow (TBF). In this study, the antivascular and antitumor effects of AC7700 were tested on primary autochthonous tumor.

Material and methods: Primary sarcomas were induced in Fischer F344 rats by a single s.c. inoculation of 3-methylcholanthrene (MC) (4 mg/0.5 ml/head). Changes in TBF due to AC7700 were measured by hydrogen clearance technique. Antitumor effects of AC7700 were evaluated by histology and tumor growth inhibition.

Results: The earliest primary tumor appeared 77 days after MC treatment and the last tumor appeared after 273 days (median, 140 days). Once tumors occurred, they continued to grow slowly and never regressed spontaneously. The mean doubling time of tumors (n = 34) during exponential growth was 12.6 +/- 9.0 days (mean +/- SD) (range, 5.4-55.9 days). Blood flow in these slow-growing autochthonous tumors decreased highly significantly from 25.2 +/- 15.5 to 4.4 +/- 3.2 ml/min/100 g (24 electrodes)(P < 0.001) within 30 min due to rapid i.v. injection (0.15 ml/min) of 10 mg/kg AC7700 and the decreased TBF did not recover during the experimental period of 6 h. On the other hand, TBF did not change significantly due to 0.9% NaCl solution (10 electrodes). In addition, TBF immediately began to decrease following slow infusion (0.005 ml/min) of 10 mg/kg AC7700 and decreased by approximately 80% (12 electrodes) at 20 min after the start of AC7700 infusion. To evaluate the antitumor effect of AC7700 on the primary tumors, 10 mg/kg AC7700 was injected i.v. to tumor-bearing rats. Although in the natural course, such tumors never stop growing, the tumor growth was strongly inhibited by AC700 (n = 5). In 2 cases, tumors never regrew for the observation period of 45 days. Biopsy and histological findings (n = 5) showed that tumors underwent extensive necrosis, as was observed previously for transplanted tumors following AC7700 administration.

Conclusion: From the present experiment it was demonstrated not only in transplanted tumors but also in carcinogen-induced autochthonous primary tumors that acute and sustained stoppage of TBF led to strong antitumor effects. The novel anticancer compound AC7700 might become a very useful therapeutic strategy against refractory cancers.