Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1994 May;120(5):286–292. doi: 10.1007/BF01236385

Combinations of interferon with platinum complexes: synergistic and antagonistic effects on growth inhibition of MCF-7 and MDA-MB231 breast cancer cells

Angela M Otto 1
PMCID: PMC12200340  PMID: 7510292

Abstract

The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB231 and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexes in vitro in an attempt to find an explanation for their more potent antitumor effects in in vivo models. Here it is shown that in both cell lines the combinations of different IFN with all three Pt complexes generally resulted in additive growth inhibition, as calculated by the product of the fraction of surviving cells obtained with each compound alone. Moreover, in MCF-7 cells natural IFNβ (nIFNβ) combined with aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-6-Pt) resulted in synergistic inhibition. This synergy could be attributed to the estrogenic property of meso-6-Pt, since the ligand and estradiol also enhanced the inhibitory effect of nIFNβ. In contrast, the combination of recombinant IFNγ and meso-6-Pt was antagonistic in MDA-MB231 cells. These results show that, in spite of the similar responses of the ER-negative and ER-positive cells to each compound alone, these cells show unexpected differences in their sensitivity to combinations of IFN and the new Pt complex meso-6-Pt.

Key words: Breast cancer, Interferon, MCF-7, MDA-MB231, Platinum complexes

Abbreviations

ER

estrogen receptor

IFN

interferon(s)

nIFN

natural interferon

rIFN

recombinant interferon

meso-4-Pt

aqua[meso-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II)

meso-6-Pt

aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]sulfatoplatinum(II)

References

  1. Berenbaum MC (1981) Criteria for analyzing interactions between biologically active agents. Adv Cancer Res 35:269–335 [DOI] [PubMed] [Google Scholar]
  2. Bhuyan BK, Adams EG, Johnson M, Crampton SL (1985) Synergistic combination of menogarol and melphalan and other two drug combinations. Invest New Drugs 3:233–244 [DOI] [PubMed] [Google Scholar]
  3. Butler WB (1984) preparing nuclei from cells in monolayer cultures suitable for counting and for following synchronized cells through the cell cycle. Anal Biochem 141:70–73 [DOI] [PubMed] [Google Scholar]
  4. Gastl G, Marth C, Leiter E, Gattringer C, Mayer I, Daxenbichler G, Flener R, Huber C (1985) Effects of human recombinant α2-interferon and γ-interferon on human breast cancer lines: dissociation of antiproliferative activity and induction of HLA-DR antigen expression. Cancer Res 45:2957–2961 [PubMed] [Google Scholar]
  5. Goldstein D, Bushmeyer SM, Witt PL, Jordan VC, Borden EC (1989) Effects of type I and II interferons on cultured human breast cancer cells: interaction with estrogen receptors and with tamoxifen. Cancer Res 49:2698–2702 [PubMed] [Google Scholar]
  6. Gust R, Schönenberg H (1993) Breast cancer-inhibiting properties of leaving group derivatives of [1,2-bis(2,6-difluor-3-hydroxyphenyl)ethylenediamineplatinum(II). Eur J Med Chem 28:117–127 [Google Scholar]
  7. Karl J, Gust R, Spruß T, Schneider MR, Schönenberger H, Engel J, Wrobel KH, Lux F, Trebert-Haeberlin S (1988) Ring-substituted [1,2-bis(4-hydroxyphenyl)-ethylenediamine]dichloroplatinum(II) complexes: compounds with a selective effect on the hormone-dependent mammary carconoma. J Med Chem 31:72–83 [DOI] [PubMed] [Google Scholar]
  8. Marth C, Mayer I, Böck G, Gastl G, Huber C, Flener R, Daxenbichler G (1985) Effects of human interferon alpha-2 and gamma on proliferation, estrogen receptor content, and sensitivity to anti-estrogens of cultured breast cancer cells. Serono Symp Publ Raven Press 24:367–371 [Google Scholar]
  9. Martino S, Samal BA, Singhakowinta A, Yoshida S, Mackenzie M, Jain J, Vaitkevicius VK (1984) A phase II study ofcis-diamminedichloroplatinum II for advanced breast cancer. Two dose schedules. J Cancer Res Clin Oncol 108:354 [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Maurer HR, Hassan HT, Tsiriyoris C, Spandidos DA (1992) Recombinant human interferons α, β and γ reduce the antiproliferative action of cytarabine in K562 human myeloid leukemia glonogenic cells. J Cancer Res Clin Oncol 118:329–333 [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Otto AM, Faderl F, Schönenberger H (1991) Dissociation of estrogenic and cytotoxic properties of an estrogen receptor binding platin complex in human breast cancer cell lines. Cancer Res 51:3217–3223 [PubMed] [Google Scholar]
  12. Pfeffer LA (1987) Cellular effects of interferons, vol 2. In: Pfeffer LA (ed) Mechanisms of interferon action. CRC, Boca Raton, Fla, pp 2–23 [Google Scholar]
  13. Porzsolt F, Otto AM, Trauschel B, Buck C, Wawer A, Schönenberger H (1989) Rationale for combining tamoxifen and interferon in the treatment of advanced breast cancer. J Cancer Res Clin Oncol 115:465–469 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Saito T, Berens ME, Welander CE (1987) Interferon-gamma and cytotoxic agents studied in combination using a soft agarose human tumor clonogenic assay. Cancer Chemother Pharmacol 19:233–239 [DOI] [PubMed] [Google Scholar]
  15. Sica G, Natoli V, Stella C, Bianco S (1987) Effect of natural beta-interferon on cell proliferation and steroid receptor level in human breast cancer cells. Cancer 60:2419–2423 [DOI] [PubMed] [Google Scholar]
  16. Smalley RV, Borden EC (1986) Interferons: current status and future directions to this prototypic biological. Springer Semin Immunpathol 9:73–83 [DOI] [PubMed] [Google Scholar]
  17. Sorenson CM, Eastman A (1988) Influence ofcis-diamminedichloroplatinum(II) on DNA synthesis and cell cycle progression in excision repair proficient and deficient Chinese hamster ovary cells. Cancer Res 48:6703–6707 [PubMed] [Google Scholar]
  18. Sorenson CM, Barry MA, Eastman A (1990) Analysis of events associated with cell cycle arrest at G2 and cell death induced by cisplatin. J Natl Cancer Inst 82:749–755 [DOI] [PubMed] [Google Scholar]
  19. Spiegel RJ (1987) Clinical overview of alpha interferon. Studies and future directions. Cancer 59:626–631 [DOI] [PubMed] [Google Scholar]
  20. Taylor-Papadimitriou J, Shearer M, Balkwill FR, Fantes KH (1982) Effects of HuIFN-α2 and HuIFN-α (Namalwa) on breast cancer cells grown in culture and as xenografts in the nude mouse. J Interferon Res 2:479–491 [DOI] [PubMed] [Google Scholar]
  21. Wadler S, Schwartz E (1990) Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human maliginancies: a review. Cancer Res 50:3473–3486 [PubMed] [Google Scholar]
  22. Wolf LM, Leitzel KE, Pegg AE, Harvey HA, Lipton A (1985) The in vitro interaction of α-difluoromethyl ornithine (DMFO) and several interferons on human cell lines. J Biol Response Mod 4:391–395 [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES