Differential relationship between changes in tumour size and microcirculatory functions induced by therapy with an antivascular drug and with cytotoxic drugs: implications for the evaluation of therapeutic efficacy of AC7700 (AVE8062)

A novel combretastatin A-4 derivative, AC7700, which is now in Phase I clinical trials under a new code, AVE8062, has shown strong antitumour effects against solid tumours in rodents because of its powerful and continued stanching of the tumour blood flow (TBF). Despite the strong tumour-suppressing qualities of AC7700, it does not produce an immediate reduction in tumour size. To elucidate the reason for this effect, we investigated the relationship between the change in tumour size in Sato lung carcinoma (SLC) and circulatory functions after therapy with AC7700, doxorubicin (Adriamycin [ADR]), or mitomycin C (MMC). To measure time-lapse changes in TBF with the hydrogen clearance method at the same site after drug administration, we developed a new apparatus for keeping electrodes within a tumour. AC7700 led to the destruction of both cancer cells and tumour vessels by interrupting the supply of nutrients. Intravenous (i.v.) administration of fluorescent dyes after AC7700 treatment revealed no fluorescence within the tumour vessels, which confirmed that the tumour microcirculation had been completely blocked. In contrast, ADR led to the destruction of SLC tumour cells, but did not have the same effect on tumour vessels. Intravenously administered fluorescent dyes immediately reached the tumour, which indicated that the tumour vasculature remained intact, and the TBF remained at the preadministration level, even 6 days after ADR treatment. In addition, although the size of the tumour increased slightly for 2 days with ADR treatment, possibly because of swelling of the cancer cells, thereafter it continued to decrease. MMC had virtually no effect on SLC tumour cells, tumour size or tumour vessels. We conclude that changes in tumour size brought about by cancer chemotherapy depend not only on the sensitivity of the cancer cells to the drug in question, but also on the nature of changes in the microcirculatory functions of the tumour brought about by the therapy. When both tumour cells and the tumour vasculature are destroyed, the effectiveness of therapy can not be determined from changes in tumour size alone.