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Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia

  • Original Articles
  • Cross-Resistance, Cisplatin-Resistant P388 Leukemia
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Summary

Since 1978, over 50 clinically useful antitumor drugs or new candidate antitumor agents have been evaluated in vivo against cisplatin-resistant P388 leukemia (P388/DDPt) in our laboratories. Analysis of this data base has yielded insights into the cross-resistance, collateral sensitivity, and mechanisms of resistance of P388/DDPt. P388/DDPt was cross-resistant or marginally crossresistant to eight agents [carmethizole·HCl, rhizoxin, dibromodulcitol, spirohydantoin mustard, hepsulfam, arabinosyl-5-azacytosine (ara-AC), tiazofurin, and deoxyspergualin]. Of these eight agents, the latter six have entered various phases of clinical trials. For these trials, it may be important to exclude or to monitor with extra care patients who have previously been treated with cisplatin. P388/DDPt was collaterally sensitive to six agents [fludarabine phosphate (2-F-ara-AMP), amsacrine (AMSA), mitoxantrone, etoposide (VP-16), batracylin, and flavone acetic acid] and, possibly, to two others (merbarone and echinomycin). These observations of collateral sensitivity suggest that a combination of cisplatin plus any one of these drugs might exhibit therapeutic synergism. Therapeutic synergism has been observed in animal models for combinations of cisplatin plus VP-16, AMSA, or mitoxantrone. The observation of collateral sensitivity for P388/DDPt to four agents (AMSA, mitoxantrone, merbarone, and VP-16) that have been reported to interact with DNA topoisomerase II suggests the possible involvement of the latter in cisplatin resistance. Both the increased sensitivity of P388/DDPt to these agents and a portion of its resistance to cisplatin could be the result of an increase in DNA topoisomerase II activity.

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Abbreviations

AMSA:

amsacrine

ara-AC:

arabinosyl-5-azacytosine

DTP:

Developmental Therapeutics Program

DCT:

Division of Cancer Treatment

2-F-ara-AMP:

fludarabine phosphate

GSH:

glutathione

ILS:

increase in life span

LD10 :

dose producing lethality in 10% of the test group

NCI:

National Cancer Institute

P388/DDPt:

cisplatin-resistant P388 leukemia

P388/0:

cisplatin-sensitive P388 leukemia

VP-16:

etoposide

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Authors and Affiliations

  1. Chemotherapy and Toxicology Research, Southern Research Institute, 35255-5305, Birmingham, AL, USA

    William R. Waud, Steadman D. Harrison Jr., Karen S. Gilbert, W. Russell Laster Jr. & Daniel P. Griswold Jr.

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  1. William R. Waud
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  2. Steadman D. Harrison Jr.
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  3. Karen S. Gilbert
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  4. W. Russell Laster Jr.
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  5. Daniel P. Griswold Jr.
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Waud, W.R., Harrison, S.D., Gilbert, K.S. et al. Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia. Cancer Chemother. Pharmacol. 27, 456–463 (1991). https://doi.org/10.1007/BF00685160

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  • DOI: https://doi.org/10.1007/BF00685160

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