TY - JOUR
T1 - Differential relationship between changes in tumour size and microcirculatory functions induced by therapy with an antivascular drug and with cytotoxic drugs
T2 - Implications for the evaluation of therapeutic efficacy of AC7700 (AVE8062)
AU - Hori, K.
AU - Saito, S.
AU - Sato, Y.
AU - Akita, H.
AU - Kawaguchi, T.
AU - Sugiyama, K.
AU - Sato, H.
N1 - Funding Information:
The authors thank the late Dr Haruo Sato, an emeritus professor of Tohoku University, who died on July 18, 2002, for his longstanding guidance and critical advice regarding the present research, and Ms. H. Oikawa for her expert technical assistance. This work was supported, in part, by a Grant-in-Aid for (2000-Designated Research-1) Cancer Research from the Ministry of Health, Labour and Welfare; by a Grant-in-Aid (No. 14030005) for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan; and by the Haruo Sato Fund for Yoshida Sarcoma and Ascites Hepatoma Memorial.
PY - 2003/9
Y1 - 2003/9
N2 - 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.
AB - 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.
KW - AVE8062
KW - Antitumour
KW - Combretastatin A-4
KW - Microcirculation
KW - Tumour blood flow
KW - Tumour vessel
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U2 - 10.1016/S0959-8049(03)00429-5
DO - 10.1016/S0959-8049(03)00429-5
M3 - Article
C2 - 12932676
AN - SCOPUS:0142121501
VL - 39
SP - 1957
EP - 1966
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 13
ER -