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Modification of methyliminodiacetato-trans-R, R-1,2-diamminocyclohexane platinum(II) pharmacology using a platinum-specific monoclonal antibody

  • Original Articles
  • cis-Platinum(II) Monoclonal Antibody, Pharmacology
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Summary

Platinum complexes are extremely active chemotherapeutic agents. A murine monoclonal antibody designated 1C1 was developed that binds to the thirdgeneration platinum complex methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum(II) (MIDP). Competitive enzyme-linked immunosorbent assay (ELISA) shows that antibody 1C1 binds preferentially to the 1,2-diamminocyclohexane (DACH) side-chain of the platinum complex, although non-DACH-containing platinum complexes can compete for binding at high concentrations. When tested against MCF-7 breast carcinoma cells, the 1C1-MIDP complex caused 50% growth inhibition at 0.63 μg Pt/ml, whereas MIDP alone caused 50% growth inhibition at a concentration of 0.16 μg Pt/ml. Pharmacokinetic studies in rats using [3H]-MIDP showed that the drug was cleared triphasically from plasma, with elimination-phase half-lives (t1/2) of 1.2, 10.2, and 243 min for α, β, and γ phases, respectively. The MIDP-1C1 complex was cleared with longer half-lives of 5, 26, and 291 min, respectively. The overall clearance rate from plasma of the MIDP-1C1 complex was 10-fold lower than that of MIDP alone (0.37 vs 3.01 ml/kgxmin). Tissue concentrations of [3H]-MIDP 3 h after administration showed that 1C1 antibody prevented MIDP distribution to most organs and dramatically reduced [3H] concentration in the intestine, liver, kidney, heart, and skeletal muscles. Studies are under way to determine the relative therapeutic activity of the 1C1 antibody-MIDP complex and assess whether the 1C1 antibody may be useful for antibodydirected delivery of platinum complexes to tumors.

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Abbreviations

MIDP :

methyliminodiacetato-trans-R-R-1,2-diamminocyclohexane platinum(II)

MTT :

2,5-diphenyltetrazolium bromide thiazolyl blue

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Authors and Affiliations

  1. Department of Clinical Immunology and Biological Therapy, The University of Texas, M. D. Anderson Cancer Center, 77030, Houston, Texas, USA

    Michael G. Rosenblum, James L. Murray & Sarah Stuckey

  2. Department of Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, 77030, Houston, Texas, USA

    Robert A. Newman & Abdul R. Khokhar

  3. Department of Biochemistry, University of North Carolina, 27514, Chapel Hill, NC, USA

    Stephen Chaney

Authors
  1. Michael G. Rosenblum
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  2. James L. Murray
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  3. Sarah Stuckey
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  4. Robert A. Newman
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  5. Stephen Chaney
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  6. Abdul R. Khokhar
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Supported in part by NIH grant CA 41581 to ARK

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Rosenblum, M.G., Murray, J.L., Stuckey, S. et al. Modification of methyliminodiacetato-trans-R, R-1,2-diamminocyclohexane platinum(II) pharmacology using a platinum-specific monoclonal antibody. Cancer Chemother. Pharmacol. 25, 405–410 (1990). https://doi.org/10.1007/BF00686050

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  • DOI: https://doi.org/10.1007/BF00686050

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