Cancer Chemotherapy and Pharmacology

, Volume 14, Issue 1, pp 30–33 | Cite as

Inhibition of spontaneous and experimental tumor metastasis by the calcium antagonist verapamil

  • Takashi Tsuruo
  • Harumi Iida
  • Fusao Makishima
  • Takao Yamori
  • Hironori Kawabata
  • Shigeru Tsukagoshi
  • Yoshio Sakurai
Original Articles Verapamil, Tumor Metastasis

Summary

Verapamil, a calcium antagonist, inhibited both experimental (IV inoculation of tumor cells) and spontaneous metastasis (SC inoculation) of the highly metastatic B16 melanoma and colon adenocarcinoma 26 cell lines. Verapamil treatment resulted in a maximum 80% inhibition of metastases, the degree of inhibition varying among the different metastatic systems. Verapamil inhibited platelet aggregation induced by these tumor cell lines, the patterns of inhibition being different for B16 melanoma and colon adenocarcinoma. The inhibition of platelet aggregation induced by tumor cells is proposed as a mechanism by which the calcium antagonist exerts its antime-tastatic effect. These results, together with our previous findings that calcium antagonists can increase the cytotoxicity of drugs in tumor cells with induced or inherent drug resistance by inhibiting outward transport of the drug, indicate that calcium antagonists have potential as a new class of adjuvant agents in the field of cancer chemotherapy.

Keywords

Tumor Cell Verapamil Platelet Aggregation Tumor Cell Line Calcium Antagonist 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bando H, Yamashita T, Tsubura E (1984) Effects of antiplatelet agents on pulmonary metastasis. Gann 74:284Google Scholar
  2. 2.
    Gasic GF, Gasic TB, Galanti N, Johnson T, Murphy S (1973) Platelet tumor cell interactions in mice. The role of platelets in the spread of malignant diseases. Int J Cancer 11:704Google Scholar
  3. 3.
    Gastpar H (1977) Platelet-cancer cell interaction in metastatic formation: a possible metastatic therapeutic approach to metastasis prophylaxis. J Med 8:103Google Scholar
  4. 4.
    Hagmar B, Norrby K (1970) Evidence for effects of heparin on cell surface influencing experimental metastasis. Int J Cancer 5:72Google Scholar
  5. 5.
    Hart IR (1979) Selection and characterization of invasive variant of the B16 melanoma. Am J Pathol 97:587Google Scholar
  6. 6.
    Hilgard P, Heller H, Schmidt CG (1976) The influence of platelet aggregation inhibitors on metastasis formation in mice (3LL). Z Krebsforsch 86:243Google Scholar
  7. 7.
    Honn KV, Onoda JM, Giglio CA, Sloane BF (1983) Calcium channel blocker: Potential antimetastatic agents. Proc Soc Exp Biol Med 174:16Google Scholar
  8. 8.
    Honn KV, Onoda JM, Diglio CA, Carufel MM, Taylor JD, Sloane BF (1984) Inmbition of tumor cell-platelet interactions and tumor metastasis by the calcium channel blocker, nimodipine. Clin Exp Metastasis 5:61Google Scholar
  9. 9.
    Kohga S (1978) Thromboplastic and fibrinolytic activities of ascites tumor cells of rats, with reference to their role in metastasis formation. Gann 69:461Google Scholar
  10. 10.
    Kohga S, Kinjo M, Tanaka K, Ogawa H, Ishihara M, Tanaka N (1981) Effects of 5-(2-chlorobenzyl) 4, 5, 6, 7-tetrahydrothieno [3, 2-C] pyridine hydrochloride (Tichlopidine), a platelet aggregation inhibitor, on bloodborne metastasis. Cancer Res 41:4710Google Scholar
  11. 11.
    Mussoni L, Poggi A, DeGaestano G, Donati MB (1978) Effect of ditazole, an inhibitor of platelet aggregation on a metastasizing tumor in mice. Br J Cancer 37:126Google Scholar
  12. 12.
    Ono H, Kimura M (1981) Effect of Ca2+ antagonistic vasodilators, diltiazem, nifedipine, perboxiline, and verapamil on platelet aggregation in vitro. Arzneim Forsch 31:113Google Scholar
  13. 13.
    Tanaka N, Ashida S, Tohgo A, Ogawa H (1982) Platelet-aggregating activities of metastasizing tumor cells. Invasion Metastasis 2:289Google Scholar
  14. 14.
    Tohgo A, Tanaka N, Ashida S, Ogawa H (1983) Platelet-aggregating activities of metastasizing tumor cells. II. Variety of the aggregation mechanisms. Invasion Metastasis 3:289Google Scholar
  15. 15.
    Tsuruo T (1983) Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics. Cancer Treat Rep 67:889Google Scholar
  16. 16.
    Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967Google Scholar
  17. 17.
    Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1982) Increased accumulation of vincristine and adriamycin in drug resistant tumor cells following incubation with calcium antagonists and calmodulin inhibitors. Cancer Res 42:4730Google Scholar
  18. 18.
    Tsuruo T, Iida H, Naganuma K, Tsukagoshi S, Sakurai Y (1983) Promotion by verapamil of vincristine responsiveness in tumor cell lines inherently resistant to the drug. Cancer Res 43:808Google Scholar
  19. 19.
    Tsuruo T, Iida H, Nojiri M, Tsukagoshi S, Sakurai Y (1983) Circumvention of vincristine and adriamycin resistance in vitro and in vivo by calcium influx blockers. Cancer Res 43:2905Google Scholar
  20. 20.
    Tsuruo T, Yamori T, Naganuma K, Tsukagoshi S, Sakurai Y (1983) Characterization of metastatic clones derived from a metastatic variant of mouse colon adenocarcinoma 26. Cancer Res 43:5437Google Scholar
  21. 21.
    Tsuruo T, Yamori T, Naganuma K, Hori K, Kawabata H, Tsukagoshi S, Sakurai Y. (1984) Metastasis after intravenous inoculation of highly metastalic variants of mouse tumors and the effects of several antitumor drugs on the tumors. Gann 75:193Google Scholar
  22. 22.
    Tsuruo T, Naganuma K, Yamori T, Kwabata H, Iida H, Tsukagoshi S, Sakurai Y (1984) Spontaneous metastasis of highly metastasis. Gann 75: (in press)Google Scholar
  23. 23.
    Vargaftig BB, Chignard M, Benveniste J (1981) Present concepts on the mechanisms of platelet aggregation. Biochem Pharmcol 30:263Google Scholar
  24. 24.
    Wood S Jr, Hilgard P (1972) Aspirin and tumor metastasis. Lancet 2:1446Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • Takashi Tsuruo
    • 1
  • Harumi Iida
    • 1
  • Fusao Makishima
    • 1
  • Takao Yamori
    • 1
  • Hironori Kawabata
    • 1
  • Shigeru Tsukagoshi
    • 1
  • Yoshio Sakurai
    • 1
  1. 1.Cancer Chemotherapy CenterJapanese Foundation for Cancer ResearchTokyoJapan

Personalised recommendations