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A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and
1Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki. nihei@ea.mbn.or.jp
Abstract:
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-alpha 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.
Insights
AC-7700, a novel combretastatin A-4 derivative, effectively suppresses solid tumor growth by inhibiting tumor perfusion. This antivascular agent shows potent activity against advanced cancers, unlike cisplatin.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Solid tumors rely on neovascularization for growth and survival.
- Targeting tumor vasculature is a promising strategy for cancer treatment.
- Combretastatin A-4 derivatives have shown antivascular properties.
Purpose of the Study:
- To evaluate the antitumor activity of AC-7700, a novel combretastatin A-4 derivative.
- To compare the efficacy of AC-7700 with cisplatin (CDDP) in preclinical cancer models.
- To determine the antivascular potential of AC-7700 against various solid tumors.
Main Methods:
- AC-7700 and CDDP were tested on established tumor models, including murine colon 26 (c26) and human LS180 adenocarcinoma.
- Antitumor activity was assessed in both early and advanced tumor growth stages.
- Tumor volume and mass were measured to determine treatment efficacy.
Main Results:
- AC-7700 demonstrated significant antitumor activity against most tested tumors, including advanced stages, unlike CDDP which was less effective in advanced tumors.
- AC-7700 exhibited a curative effect on advanced c38 tumors and was effective on orthotopically transplanted c26 tumors.
- AC-7700 suppressed tumor growth independently of host immune status, suggesting a direct antivascular mechanism.
Conclusions:
- AC-7700 is a potent novel antivascular agent with significant antitumor activity against a range of solid tumors.
- AC-7700 shows promise for treating advanced-stage cancers.
- Further clinical investigation of AC-7700 is warranted.