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Combination of etanidazole with cyclophosphamide and platinum complexes

  • Original Articles
  • Platinum Complexes, Cyclophosphamide, Etanidazole
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Summary

In an effort of improve the therapeutic efficacy and selectivity of cyclophosphamide (CTX),cis-diamminedichloroplatinum(II) (CDDP), and carboplatin (Carbo), these antitumor alkylating agents were combined with the 2-nitroimidazole drug etanidazole (ETA). As revealed by tumor-cell survival assay in the FSaIIC murine fibrosarcoma, the addition of ETA (1 g/kg, i.p.) just prior to the i.p. injection of various doses of the alkylating agents resulted in increases in the tumor-cell kill produced by each drug (CTX, 10-fold; CDDP, 20-fold; and Carbo, 5-to 15-fold), whereas toxicity to bone marrow granulocytemacrophage colony-forming units (CFU-GM) increased only about 0- to 3-fold. When CTX was combined with either CDDP or Carbo, striking increases in tumor-cell killing were observed (20- to 100-fold across the CDDP dose range and 5- to 20-fold across the dose range of Carbo), which were supra-additive for CDDP and additive for Carbo as revealed by isobologram analysis. The addition of ETA to these alkylating-agent combinations produced a further approx. 20-fold increase in tumor-cell kill for both CTX/CDDP and CTX/Carbo. This effect was greatest at the lowest dose of the platinum drug tested and was supra-additive in the case of CDDP and additive for Carbo. Following treatment with ETA/CTX/CDDP, bone marrow CFU-GM toxicity increased only about 5-fold over that of CTX/CDDP alone, but the injection of ETA/CTX/Carbo resulted in a 10- to 20-fold increase in bone marrow toxicity as compared with that obtained using CTX/Carbo alone. Tumor growth-delay studies revealed significant increases in the antitumor effect of the alkylating agents when these were given in combination with ETA. Both the ETA/CTX/CDDP and the ETA/CTX/Carbo combinations produced tumor growth delays of 23 days, which represented approx. 1.6-fold increases over those obtained using the alkylating-agent combinations alone. These results suggest that ETA could significantly improve the therapeutic efficacy of these alkylating agents, whether they therapeutic efficacy of these alkylating agents, whether they are given individually or in combination.

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Abbreviations

ETA:

etanidazole

CTX:

cyclophophamide

CDDP:

cis-diamminedichloroplatinum(II)

Carbo:

carboplatin

PBS:

phosphatebuffered saline

FBS:

fetal bovine serum

DMEM:

Dulbecco's minimal essential medium

CFU-GM:

granulocyte-macrophage colony-forming units

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, 44 Binney Street, 02 115, Boston, MA, USA

    Beverly A. Teicher & Terence S. Herman

  2. Joint Center for Radiation Therapy, 44 Binney Street, 02 115, Boston, MA, USA

    Beverly A. Teicher, Terence S. Herman, C. Norman Coleman & Emil Frei III

  3. Brigham and Women's Hospital, 75 Francis Street, 02 115, Boston, MA, USA

    C. Norman Coleman

  4. Beth Israel Hospital, 330 Brookline Avenue, 02215, Boston, MA, USA

    Lawrence Shulman

Authors
  1. Beverly A. Teicher
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  2. Terence S. Herman
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  3. Lawrence Shulman
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  4. Glenn Bubley
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  5. C. Norman Coleman
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  6. Emil Frei III
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Additional information

This work was supported by National Cancer Institute grant PO1-37859, by a grant from the Mathers Foundation, and by a grant from Bristol Myers Inc., Wallingford, Connecticut

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Teicher, B.A., Herman, T.S., Shulman, L. et al. Combination of etanidazole with cyclophosphamide and platinum complexes. Cancer Chemother. Pharmacol. 28, 153–158 (1991). https://doi.org/10.1007/BF00685502

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  • DOI: https://doi.org/10.1007/BF00685502

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