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Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Oncogene volume 18, pages 2241–2251 (1999)Cite this article

Abstract

Previous studies have demonstrated a synergistic interaction between rhuMAb HER2 and the cytotoxic drug cisplatin in human breast and ovarian cancer cells. To define the nature of the interaction between rhuMAb HER2 and other classes of cytotoxic drugs, we applied multiple drug effect/combination index (CI) isobologram analysis to a variety of chemotherapeutic drug/rhuMAb HER2 combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for rhuMAb HER2 in combination with cisplatin (CI=0.48, P=0.003), thiotepa (CI=0.67, P=0.0008), and etoposide (CI=0.54, P=0.0003). Additive cytotoxic effects were observed with rhuMAb HER2 plus doxorubicin (CI=1.16, P=0.13), paclitaxel (CI=0.91, P=0.21), methotrexate (CI=1.15, P=0.28), and vinblastine (CI=1.09, P=0.26). One drug, 5-fluorouracil, was found to be antagonistic with rhuMAb HER2 in vitro (CI=2.87, P=0.0001). In vivo drug/rhuMAb HER2 studies were conducted with HER-2/neu-transfected, MCF7 human breast cancer xenografts in athymic mice. Combinations of rhuMAb HER2 plus cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a significant reduction in xenograft volume compared to chemotherapy alone (P<0.05). Xenografts treated with rhuMAb HER2 plus 5-fluorouracil were not significantly different from 5-fluorouracil alone controls consistent with the subadditive effects observed with this combination in vitro. The synergistic interaction of rhuMAb HER2 with alkylating agents, platinum analogs and topoisomerase II inhibitors, as well as the additive interaction with taxanes, anthracyclines and some antimetabolites in HER-2/neu-overexpressing breast cancer cells demonstrates that these are rational combinations to test in human clinical trials.

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References

  • Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J and Sela M. . 1988 J. Natl. Cancer Inst. 80: 1605–1611.

  • Arteaga CL, Winnier AR, Poirier MC, Lopez-Larraza DM, Shawver LK, Hurd SD and Stewart SJ. . 1994 Cancer Res. 54: 3758–3765.

  • Baselga J, Miller W, Norton L and Mendelsohn J. . 1992 Proc. Am. Assoc. Cancer Res. 33: 2947.

  • Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller Jr WH and Mendelsohn J. . 1993 J. Natl. Cancer Inst. 85: 1327–1333.

  • Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J Rosen PP, Twaddell T, Henderson IC and Norton L. . 1996 J. Clin. Oncol. 14: 737–744.

  • Baselga J, Norton L, Albanell J, Kim YM and Mendelsohn J. . 1998 Cancer Res. 58: 2825–2831.

  • Berchuck A, Rodriguez G, Kinney RB, Soper JT, Dodge RK, Clarke-Pearson DL and Bast Jr RC. . 1991 Am. J. Obstet. Gynecol. 164: 15–21.

  • Bible KC and Kaufmann SH. . 1997 Cancer Res. 57: 3375–3380.

  • Boven E and Winograd B, eds.. 1991 The Nude Mouse Oncol. Res. CRC Press, Boca Raton, FL.

    Google Scholar 

  • Buick RN. . 1994 Cancer Chemotherapy Handbook, Dorr RT and Von Hoff, DD (eds.). Appleton & Lange: Norwalk, CN. pp. 3–14.

    Google Scholar 

  • Carter P, Presta L, Gorman CM, Ridgway JB, Henner D, Wong WL, Rowland AM, Kotts C, Carver ME and Shepard HM . 1992 Proc. Natl. Acad. Sci. USA 89: 4285–4289.

  • Chazin VR, Kaleko M, Miller AD and Slamon DJ. . 1992 Oncogene 9: 1859–1866.

  • Chou T and Talalay P. . 1984 Ad. Enzyme Reg. 22: 27–55.

  • De Santes K, Slamon D, Anderson SK, Shepard M, Fendly B, Maneval D and Press O. . 1992 Cancer Res. 52: 1916–1923.

  • Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA and Ullrich A. . 1990 Cancer Res. 50: 1550–1558.

  • Flick DA and Gifford GE. . 1984 J. Immunol. Methods 68: 167–175.

  • Gillies RJ, Didier N and Denton M. . 1986 Analytical Biochem. 159: 109–113.

  • Giovanella BC, Stehoin JS and Shepard RC. . 1977 Proceedings of the Second International Workshop on Nude Mice. Nomura T, Ohsawa N, Tamaoki N and Fujiwara K, (eds.). Univ. of Tokyo Press. pp. 475–481.

    Google Scholar 

  • Hanauske AR, Osborne CK, Chamness GC, Clark GM, Forseth BJ, Buchok JB, Arteaga CL and Von Hoff DD. . 1987 Euro. J. Cancer Clin. 23: 545–551.

  • Hancock MC, Langton BC, Chan T, Toy P, Monahan JJ, Mischak RP and Shawver LK. . 1991 Cancer Res. 51: 4575–4580.

  • Hetzel DJ, Wilson TO, Keeney GL, Roche PC, Cha SS and Podratz KC. . 1992 Gynecol. Oncol. 47: 179–185.

  • Hill AV. . 1913 Biochem. J. 7: 471–480.

  • Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard HM, Kuang W-J, Wood WI, Goeddel DV and Vandlen RL. . 1992 Science 256: 1205–1210.

  • Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM and Ullrich A. . 1989 Molec. & Cell. Biol. 9: 1165–1172.

  • Hsu S, Pegram MD, Pietras RJ, Beryt M and Dennis Slamon. . 1997 Basic Clinical Aspects Breast Cancer (abstr.) Keystone, CO.

    Google Scholar 

  • Inaba M, Kobayashi T, Tashiro T and Sakurai Y. . 1988 Jpn. J. Cancer Res. (Gann). 79: 509.

  • Klapper LN, Vaisman N, Hurwitz E, Pinkas-Kramarski R, Yarden Y and Sela M. . 1997 Oncogene 14: 2099–2109.

  • Lukes AS, Kohler MF, Pieper CF, Kerns BJ, Bentley R, Rodriguez GC, Soper JT, Clarke-Pearson DL, Bast Jr RC and Berchuck A. . 1994 Cancer 73: 2380–2385.

  • Maier LA, Xu FJ, Hester S, Boyer CM, McKenzie S, Bruskin AM, Argon Y and Bast Jr RC. . 1991 Cancer Res. 51: 5361–5369.

  • Park JW, Stagg R, Lewis GD, Carter P, Maneval D, Slamon DJ, Jaffe H and Shepard HM. . 1992 Cancer Treatment Res. 61: 193–211.

  • Pegram MD, Pietras RJ and Slamon DJ. . 1992 Proc. Am. Assoc. Cancer Res. 33: 442.

  • Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ and Slamon DJ. . 1997 Oncogene 15: 537–547.

  • Pegram MD, Lipton A, Hayes D, Weber B, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy J and Slamon DJ. . 1998 J. Clin. Oncol. 16: 2659–2671.

  • Pietras RJ, Fendly BM, Chazin VR, Pegram MD, Howell SB and Slamon DJ. . 1994 Oncogene 9: 1829–1838.

  • Press MF, Pike MC, Hung G, Zhou JY, Ma Y, George J, Dietz-Band J, James W, Slamon DJ, Batsakis JG and El-Naggas AK. . 1994 Cancer Res. 54: 5675–5682.

  • Reese DM, Arboleda J, Twaddell J, Akita R, Sliwkowski MX and Slamon DJ. . 1996 Proc. Am. Assoc. Cancer Res. 37: 51 (abstr 353).

  • Reile H, Birnbock H, Bernhardt G, Spruss T and Schonenberger H. . 1990 Analytical Biochem. 187: 262–267.

  • Rodriguez GC, Boente MP, Berchuck A, Whitaker RS, O'Briant KC, Xu F and Bast Jr, RC. . 1993 Am. J. Obstet. and Gynecol. 168: 228–232.

  • Saffari B, Jones LA, el-Naggar A, Felix JC, George J and Press MF. . 1995 Cancer Res. 55: 5693–5698.

  • Semba K, Kamata N, Toyoshima K and Yamamoto T. . 1985 Proc. Natl. Acad. Sci. USA 82: 6497–6501.

  • Sias PE, Kotts CE, Vetterlein D, Shepard M and Wong WL. . 1990 J. Immunol. Methods 132: 73–80.

  • Slamon DJ, Clark GM, Wong SJ, Levin WJ, Ullrich A and McGuire WL. . 1987 Science 235: 177–182.

  • Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A and Press MF. . 1989 Science 244: 707–712.

  • Tannock IF. . 1978 Cancer Treat Rep. 62: 1117–1133.

  • Yarden Y. . 1990 Proc. Natl. Acad. Sci. USA 87: 2569–2573.

  • Yonemura Y, Ninomiya I, Ohoyama S, Kimura H, Yamaguchi A, Fushida S, Kosaka T, Miwa K, Miyazaki I, Endou Y, Tanaka M and Sasaki T. . 1991 Cancer 67: 2914–2918.

  • Zuckier G and Tritton TR. . 1983 Exper. Cell Res. 148: 155–161.

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Authors and Affiliations

  1. Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, 90095, California, USA

    Mark Pegram, Sheree Hsu, Richard Pietras, Malgorzata Beryt, Fairooz Kabbinavar & Dennis Slamon

  2. Genentech, Inc., One DNA Way, South San Francisco, California, USA

    Gail Lewis, Mark Sliwkowski, Daniel Coombs & Deborah Baly

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  1. Mark Pegram
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Pegram, M., Hsu, S., Lewis, G. et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18, 2241–2251 (1999). https://doi.org/10.1038/sj.onc.1202526

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