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. 1987 Sep;56(3):273–278. doi: 10.1038/bjc.1987.189

Synergistic cell inactivation by cis-dichlorodiammineplatinum in combination with 1-propargyl-5-chloropyrimidin-2-one.

J M Dornish 1, E O Pettersen 1, R Oftebro 1
PMCID: PMC2002188  PMID: 3663475

Abstract

A synergistic effect with respect to inactivation of human NHIK 3025 cells cultured in vitro was displayed when treatment with cis-dichlorodiammineplatinum(II) (cis-DDP) and the mitotic inhibitor 1-propargyl-5-chloropyrimidin-2-one (NY 3170) were given in simultaneous combination. Cell inactivation was measured by loss of colony-forming ability. Treatment with NY 3170 alone produced no significant inactivation at concentrations up to 2 mM. However, treatment with NY 3170 in combination with cis-DDP induced increased cell inactivating effects equal to a doubling of either the concentration of cis-DDP or treatment time. Scheduling of NY 3170 treatment in relationship to a 1 h cis-DDP pulse revealed that synergism occurred only when the two drugs were present simultaneously. The inactivating effect of 10 microM cis-DDP in combination with 2 mM NY 3170 given to synchronized NHIK 3025 cells at various stages of the cell cycle was also determined. For cells treated in S or in G2 + M cell survival was reduced by a factor of 5 after a 1 h treatment with the drug combination as compared to similar treatment with cis-DDP alone. The cells appeared to be most sensitive at the time of initiation of DNA synthesis. Here cell survival was reduced by a factor of 100 following treatment with the drug combination than following treatment with cis-DDP alone. Measurement of cell-associated platinum by atomic absorption spectroscopy indicated that cellular uptake of cis-DDP was increased when NY 3170 was simultaneously present during drug treatment.

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Selected References

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  1. Bergerat J. P., Drewinko B., Corry P., Barlogie B., Ho D. H. Synergistic lethal effect of cis-dichlorodiammineplatinum and 1-beta-D-arabinofuranosylcytosine. Cancer Res. 1981 Jan;41(1):25–30. [PubMed] [Google Scholar]
  2. Byfield J. E., Calabro-Jones P. M. Carrier-dependent and carrier-independent transport of anti-cancer alkylating agents. Nature. 1981 Nov 19;294(5838):281–283. doi: 10.1038/294281a0. [DOI] [PubMed] [Google Scholar]
  3. Davidson J. P., Faber P. J., Fischer R. G., Jr, Mansy S., Peresie H. J., Rosenberg B., VanCamp L. "Platinum-pyrimidine blues" and related complexes: a new class of potent antitumor agents. Cancer Chemother Rep. 1975 Mar-Apr;59(2 Pt 1):287–300. [PubMed] [Google Scholar]
  4. Dornish J. M., Melvik J. E., Pettersen E. O. Reduced cellular uptake of cis-dichlorodiammine-platinum by benzaldehyde. Anticancer Res. 1986 Jul-Aug;6(4):583–588. [PubMed] [Google Scholar]
  5. Dornish J. M., Oftebro R. Structure-activity relationship of 1-propargyl-5-halopyrimidin-2-ones. Metaphase arresting properties and competitive inhibition of colchicine binding to tubulin. Invest New Drugs. 1983;1(3):203–211. doi: 10.1007/BF00208891. [DOI] [PubMed] [Google Scholar]
  6. Dornish J. M., Pettersen E. O., Oftebro R. Interaction of 1-propargyl-5-chloropyrimidin-2-one (a metahalone) with rat brain tubulin. Biochim Biophys Acta. 1984 Feb 14;797(2):156–162. doi: 10.1016/0304-4165(84)90117-x. [DOI] [PubMed] [Google Scholar]
  7. Dornish J. M., Pettersen E. O., Oftebro R., Melvik J. E. Reduction of cis-dichlorodiammineplatinum-induced cell inactivation by benzaldehyde. Eur J Cancer Clin Oncol. 1984 Oct;20(10):1287–1293. doi: 10.1016/0277-5379(84)90258-x. [DOI] [PubMed] [Google Scholar]
  8. Dornish J. M., Pettersen E. O. Protection from cis-dichlorodiammineplatinum-induced cell inactivation by aldehydes involves cell membrane amino groups. Cancer Lett. 1985 Dec;29(3):235–243. doi: 10.1016/0304-3835(85)90133-8. [DOI] [PubMed] [Google Scholar]
  9. Gacek M., Undheim K., Oftebro R., Laland S. G. Metahalones, a new class of metaphase inhibitors. FEBS Lett. 1979 Feb 15;98(2):355–358. doi: 10.1016/0014-5793(79)80216-1. [DOI] [PubMed] [Google Scholar]
  10. Gale G. R., Atkins L. M., Meischen S. J., Smith A. B., Walker E. M., Jr Chemotherapy of advanced L1210 leukemia with platinum compounds in combination with other antitumor agents. Cancer Treat Rep. 1977 May-Jun;61(3):445–450. [PubMed] [Google Scholar]
  11. Gale G. R., Morris C. R., Atkins L. M., Smith A. B. Binding of an antitumor platinum compound to cells as influenced by physical factors and pharmacologically active agents. Cancer Res. 1973 Apr;33(4):813–818. [PubMed] [Google Scholar]
  12. Lindmo T., Pettersen E. O. Delay of cell cycle progression after X-irradiation of synchronized populations of human cells (NHIK 3025) in culture. Cell Tissue Kinet. 1979 Jan;12(1):43–57. doi: 10.1111/j.1365-2184.1979.tb00112.x. [DOI] [PubMed] [Google Scholar]
  13. PUCK T. T., CIECIURA S. J., FISHER H. W. Clonal growth in vitro of human cells with fibroblastic morphology; comparison of growth and genetic characteristics of single epithelioid and fibroblast-like cells from a variety of human organs. J Exp Med. 1957 Jul 1;106(1):145–158. doi: 10.1084/jem.106.1.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Pettersen E. O., Bakke O., Lindmo T., Oftebro R. Cell cycle characteristics of synchronized and asynchronous populations of human cells and effect of cooling of selected mitotic cells. Cell Tissue Kinet. 1977 Nov;10(6):511–522. doi: 10.1111/j.1365-2184.1977.tb00309.x. [DOI] [PubMed] [Google Scholar]
  15. Pettersen E. O., Nome O., Rønning O. W., Oftebro R. Effects of benzaldehyde on survival and cell-cycle kinetics of human cells cultivated in vitro. Eur J Cancer Clin Oncol. 1983 Apr;19(4):507–514. doi: 10.1016/0277-5379(83)90114-1. [DOI] [PubMed] [Google Scholar]
  16. Schabel F. M., Jr, Trader M. W., Laster W. R., Jr, Corbett T. H., Griswold D. P., Jr cis-Dichlorodiammineplatinum(II): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1459–1473. [PubMed] [Google Scholar]
  17. Veselý J. Synergistic effect of cis-dichlorodiammineplatinum and 5-aza-2'-deoxycytidine on mouse leukemic cells in vivo and in vitro. Int J Cancer. 1982 Jan 15;29(1):81–85. doi: 10.1002/ijc.2910290114. [DOI] [PubMed] [Google Scholar]
  18. Wibe E. Age-dependent cell inactivation by vincristine alone or in combination with 1-propargyl-5-chloropyrimidin-2-one. Cancer Res. 1980 Jun;40(6):2069–2073. [PubMed] [Google Scholar]
  19. Wibe E., Oftebro R. A study of factors related to the action of 1-propargyl-5-chloropyrimidin-2-one (NY 3170) and vincristine in human multicellular spheroids. Eur J Cancer Clin Oncol. 1981 Sep;17(9):1053–1059. doi: 10.1016/s0277-5379(81)80013-2. [DOI] [PubMed] [Google Scholar]
  20. Wibe E., Oftebro R., Christensen T., Laland S. G., Pettersen E. O., Lindmo T. Inhibitory effects of the new mitotic inhibitor 5-chloropyrimidin-2-one and of vincristine on human cells in vitro. Cancer Res. 1978 Mar;38(3):560–565. [PubMed] [Google Scholar]
  21. Wibe E., Oftebro R. Inactivation by the mitotic inhibitor NY 3170 of human cells in vitro. Br J Cancer. 1979 Aug;40(2):222–227. doi: 10.1038/bjc.1979.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wibe E., Oftebro R., Laland S. G., Pettersen E. O., Lindmo T. Cell-cycle inhibitory effects of the mitotic inhibitor NY 3170 on human cells in vitro. Br J Cancer. 1979 Apr;39(4):391–397. doi: 10.1038/bjc.1979.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Zwelling L. A., Kohn K. W. Mechanism of action of cis-dichlorodiammineplatinum(II). Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1439–1444. [PubMed] [Google Scholar]

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