Antitumor Effects due to Irreversible Stoppage of Tumor Tissue Blood Flow: Evaluation of a Novel Combretastatin A‐4 Derivative, AC7700

Abstract

The relation between tumor tissue blood flow (tBF) reduction and antitumor effects was investigated. Changes in tBF of normal tissues (liver, kidney cortex, bone marrow and brain cortex) and tumors (Yoshida sarcoma subline, LY80 and Sato lung carcinoma, SLC) due to i.v. administration of AC7700 (1, 3, 10 mg/kg), one of the combretastatin A-4 derivatives, were measured with the hydrogen clearance method. The change in blood flow in tumor microfoci was also observed directly using a rat transparent chamber. Chemotherapy against the solid tumors (LY80, SLC) was performed by administering AC7700 7 times at intervals of 3 days and the effect on the tumor growth, the histological effect, the effect on lymph node metastasis and the survival rate were investigated. Tumor tBF showed a dose-dependent response to AC7700. Although tumor tBF decreased markedly at a dose of 1 mg/kg, it tended to recover partly within several hours. At 10 mg/kg, however, tumor tBF completely stopped within approximately 30 min and never recovered in many regions. The irreversible stoppage of tumor tBF was observed in large s.c. tumors and in microfoci as well. On the other hand, in normal tissues, tBF changes due to AC7700 were not uniform. In the liver, although tBF decreased by approximately 50% at 10 mg/kg AC7700, it recovered within 8 h. In the brain, although the mean maximum reduction was 35%, the blood flow recovered to the original level within 24 h. The blood flow in the kidney cortex did not change at all. In the bone marrow, tBF decreased by approximately 80%. Generally, the blood flow reduction in normal tissues tended to be reversible. The effect on tumor growth and the histological effect were also dependent on the dose of AC7700. The tumor growth was markedly inhibited by 10 mg/ kg AC7700 and extensive necrosis was induced. Lymph node metastases were significantly inhibited and survival was prolonged significantly. In the control group, all 8 SLC tumor-bearing rats died of cancer, the presence of which was verified by gross and microscopic evaluation, within 45 days after tumor implantation. On the other hand, in the treated group, 2 of 8 rats recovered completely and survived. No obvious side effects such as body weight loss, anemia or diarrhea were observed at the dose used in this experiment. From these results, we conclude that strong antitumor effects are obtained by stopping tumor tBF irreversibly and by shutting off the nutritional supply into tumor tissue. AC7700 has been demonstrated to be a promising anticancer compound which has such an action.

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

“…In the case of tumours in the liver, muscle and lymph nodes, TBF was completely stopped within 1 h. When blood flow changes in the normal liver and the hepatic tumour were measured simultaneously, TBF was almost completely stanched by AC7700, whereas the blood flow decrease in the normal liver was 30 -40% at the maximum and was reversible (data not shown). The rate of decrease and the pattern of recovery of liver blood flow were almost the same as those reported previously (Hori et al, 1999). The TBF decrease caused by AC7700 in the renal tumour was completely tumour specific.…”

“…In all tumours, AC7700-induced TBF cessation was completed within 30 -60 min after i.v. administration of the drug and was maintained during the experimental period of 6 h. This result was analogous to that obtained with subcutaneous tumours (Hori et al, 1999). In tumours growing in muscle, liver, and lymph Experimental Therapeutics nodes, the TBF decreased almost to zero.…”

“…For colon 26 adenocarcinoma, AC7700 showed stronger antitumour effects, compared with CS A-4-P, at a dose that was an order of magnitude lower than that of CS A-4-P (Nihei et al, 1999a). Our research group also demonstrated that AC7700 has a remarkable therapeutic effect against not only transplanted tumours (Hori et al, 1999;Nihei et al, 1999b) but also methylcholanthrene-induced autochthonous primary tumours (Hori et al, 2001), and we determined that the effect is caused by irreversible stoppage of TBF (Hori et al, 1999).…”

“…administration of AC7700 strongly stanched TBF not only in subcutaneous tumours (Hori et al, 1999(Hori et al, , 2001) but also in tumours growing in various kinds of tissues and organs, including lymph node metastases, and that the stanched TBF suppressed tumour growth in all regions of the body. In all tumours, AC7700-induced TBF cessation was completed within 30 -60 min after i.v.…”

“…Change in TBF caused by AC7700 or 0.9% NaCl solution By means of the same method as described previously (Hori et al, 1999), the TBF in tumours growing within the liver, stomach, kidney, muscle, and lymph nodes was measured at multiple time points (i.e., 10, 30, and 60 min, and every subsequent hour) until 6 h after AC7700 or 0.9% NaCl solution administration.…”