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Discrepancy between cytotoxicity and DNA interstrand crosslinking of carboplatin and cisplatin in vivo

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Abstract

We used the method of alkaline elution to compare quantitatively the DNA lesions produced by cisplatin and carboplatin in the AKR leukemia in vivo. These data were compared with cytotoxicity of each drug in the same animal model and in a solid tumor murine model (colon 26).

DNA-protein and DNA-DNA interstrand crosslinks were formed in similar proportions by both drugs when peak values of crosslinking were compared. No clear difference in the rate of formation of both types of crosslinks could be observed between these drugs.

On a molar basis a 3- to 4-fold more carboplatin had to be given to obtain equivalent frequencies of both types of crosslinks. In contrast, to obtain equitoxicity in the same animal tumor model, 13 fold higher doses of carboplatin had to be given. This difference in cytotoxicity between both drugs is comparable to the difference measured in colon 26 in vivo (16 fold). Both values are in the range of literature data (10–25 fold) dealing with the relative potency of cisplatin and carboplatin in murine tumor models.

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Abbreviations

DIC:

DNA-DNA Interstrand Crosslinks

DPC:

Protein-DNA Crosslinks

EDTA:

Ethylene-Diammine-Tetra-Acetic Acid

PK:

Proteinase K

PSA:

Puck's Saline A

SSB:

Single Strand Breaks

ILS:

Increase in Life Span

Carboplatin-Cis-(diammino)(1,1-cyclobutane-dicarboxylato)-Platinum (II), Cisplatin:

Cis-Diamminedichloroplatinum (II)

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Author notes

  1. Wilfried DeNeve

    Present address: Radiotherapy, Academic Hospital V. U.B., Laarbeeklaan 101, 1090, Brussels, Belgium

Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology and Oncology, Wayne State University School of Medicine, 48201, Detroit, MI, USA

    Wilfried DeNeve, Frederick Valeriote, Efstathios Tapazoglou, Carleen Everett, Anup Khatana & Thomas Corbett

Authors
  1. Wilfried DeNeve
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  2. Frederick Valeriote
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  3. Efstathios Tapazoglou
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  4. Carleen Everett
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  5. Anup Khatana
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  6. Thomas Corbett
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Additional information

Supported by an award from the Belgian Work against Cancer.

American Cancer Society Cancer Development Award Recipient.

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DeNeve, W., Valeriote, F., Tapazoglou, E. et al. Discrepancy between cytotoxicity and DNA interstrand crosslinking of carboplatin and cisplatin in vivo . Invest New Drugs 8, 17–24 (1990). https://doi.org/10.1007/BF00216920

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