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Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11

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Abstract

The anti-metastatic efficacy of MMI-166, which is a selective matrix metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using two metastasis models of human gastrointestinal cancer cells. In the liver metastasis model, C-1H human colon cancer cells were injected into the spleen of athymic BALB/c nude mice. Daily oral (p.o.) dosing of MMI-166 at 200 mg/kg starting 1 day after tumor inoculation led to a significantly prolonged survival effect by inhibiting liver metastasis of C-1H tumor cells. CPT-11 (5 or 20 mg/kg) was administered intraperitoneally (i.p.) three times on day 3, day 7 and day 11 and also improved the survival of tumor-inoculated mice compared with the vehicle control. When MMI-166 was combined with CPT-11, the anti-metastatic efficacy was significantly augmented. Moreover, long tumor-free survival was noted in two of eight mice that were given the combination therapy but not either MMI-166 or CPT-11 monotherapy. In the peritoneal dissemination model, TMK-1 human gastric cancer cells were injected i.p. into nude mice. While both MMI-166, administered daily p.o. from day 1 at 200 mg/kg, and CPT-11, administered intravenously (i.v.) three times, inhibited the tumor dissemination and growth, the combination therapy of MMI-166 plus CPT-11 showed a greater inhibitory effect than each monotherapy. A hematotoxicity study demonstrated that CPT-11 alone significantly decreased the number of white blood cells (WBC) and bone marrow cells (BMC) in the mice during treatment, while the daily administration of MMI-166 alone had no such effect. More importantly, the combination therapy of MMI-166 with CPT-11 did not augment the hematotoxicity caused by CPT-11. An in vitro cytotoxicity study showed that MMI-166 itself neither has direct cytotoxicity in C-1H and TMK-1 tumor cells, nor does it augment the cytotoxicity of SN-38, an active form of CPT-11. The findings indicate that the augmented anti-metastatic efficacy in combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive or synergistic effect of anti-metastatic activities with different mechanisms. In conclusion, we demonstrated that the anti-metastatic efficacy against C-1H colon cancer and TMK-1 gastric cancer were augmented by the combination therapy of MMI-166, an orally active MMP inhibitor, with CPT-11. However, the hematotoxicity caused by CPT-11 was not augmented in the combination with MMI-166. Thus, the combination therapy of MMI-166 and CPT-11 exhibited potent anti-metastatic efficacy without increased hematotoxicity. These results point to the clinical advantage of using MMI-166 in combination with CPT-11.

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Authors and Affiliations

  1. Shionogi Research Laboratories, Japan

    Hideo Maki, Kanji Hojo, Hidekazu Tanaka, Takuko Yamada Sawada, Ryuji Maekawa & Takayuki Yoshioka

  2. Pharmaceutical Development Division, Shionogi & Co Ltd, Fukushima-ku, Osaka, Japan

    Takuko Yamada Sawada

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  1. Hideo Maki
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  2. Kanji Hojo
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  3. Hidekazu Tanaka
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  5. Ryuji Maekawa
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  6. Takayuki Yoshioka
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Maki, H., Hojo, K., Tanaka, H. et al. Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11. Clin Exp Metastasis 19, 519–526 (2002). https://doi.org/10.1023/A:1020321210623

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