Yukio Nihei

Syntheses and antitumor activity of cis-restricted combretastatins : 5-membered heterocyclic analogues

A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.

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

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.

Evaluation of Antivascular and Antimitotic Effects of Tubulin Binding Agents in Solid Tumor Therapy

Tubulin binding agents (TBAs) reduce tumor perfusion and inhibit mitosis of tumor cells in solid tumors, but it is not clear which effects contribute to the suppression of solid tumor growth. We evaluated the antivascular and antimitotic effects of several TBAs, combretastatin A‐4 (CS A‐4) phosphate, AC‐7700, a novel CS A‐4 derivative, colchicine, E7010, and vinblastine, on subcutaneous (s.c.) murine colon26 adenocarcinoma (c26). Tolerable doses of vinblastine and E7010 strongly inhibited tumor growth and induced mitotic arrest of tumor cells without affecting tumor perfusion. Colchicine had no effect on tumor growth and perfusion. When the injected dose was increased to the lethal range, however, these drugs markedly reduced tumor perfusion and caused necrosis of tumor tissue. Within the tolerable dose range, AC‐7700 both strongly suppressed tumor growth and reduced tumor perfusion, and CS A‐4 phosphate also exhibited a moderate antivascular effect. To evaluate the contribution of antivascular activity of TBAs to tumor growth suppression, excluding their direct cytotoxic effect on tumor cells, we established c26/acr, which is resistant to TBAs in vitro. Although E7010 showed a reduced suppressive effect on s.c. c26/acr tumor growth as compared with its effect on wild‐type c26, AC‐7700 remained potent against both cell lines. These results indicate that TBAs exert antivascular and antimitotic effects on solid tumors with marked differently effective dose ranges from agent to agent, and that the antivascular effect of TBAs inhibits solid tumor growth independently of the direct cytotoxic effect on tumor cells.

Novel B-ring modified combretastatin analogues : Syntheses and antineoplastic activity

A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.

A Novel Combretastatin A-4 Derivative, AC-7700, Shows Marked Antitumor Activity against Advanced Solid Tumors and Orthotopically Transplanted Tumors

AC‐7700, a novel combretastatin A‐4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC‐7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early‐stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2–0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC‐7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC‐7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor‐α production, AC‐7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC‐7700 is a novel antivascular agent that may have potent activity against advanced‐stage cancer in the clinical setting.

Combination effect of AC-7700, a novel combretastatin A-4 derivative, and cisplatin against murine and human tumors in vivo

The in vivo combination effect of AC‐7700, a novel combretastatin A‐4 derivative, and cisplatin (CDDP) was examined. The combination of AC‐7700 and CDDP increased antitumor activity against murine colon 26 tumor in mice and cured the mice. This combination effect was found over wide dosage ranges of AC‐7700 (20–80 mg/kg) and CDDP (2.5–5 mg/kg). Moreover, this combination augmented antitumor activity against murine S180 and M109 tumors, and human LX‐1 and LS180 tumor xenografts in mice. The effect was the strongest when AC‐7700 and CDDP were administered simultaneously. To study this combination effect we measured the concentrations of CDDP in tumors, plasma and kidneys of the mice with colon 26 tumor. In the combination with AC‐7700, the concentration of CDDP in the tumors increased from 0.5 to 96 h after administration, but did not change or decrease in plasma or kidneys. Against human LS180 xenografts in mice, the combination similarly increased the concentration of CDDP in the tumors. These results suggest that AC‐7700 may specifically augment the accumulation of CDDP in tumors, and thus has the potential to be useful in combination chemotherapy with CDDP. (Cancer Sci 2003; 94: 200–204)