Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells

Allan Y. Chen, Chiang Yu, Leroy-Fong Liu, Monroe E. Wall, Mansukh C. Wani, Leroy F. Liu

Research output: Contribution to journalArticle

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Abstract

In order to understand the high efficacy of camptothecin derivatives against human colon tumor xenografts in nude mice, we have studied the transport properties of camptothecin derivatives across cellular membranes of MDR1-overexpressing cells. MDR1 overexpression was shown to have little effect on camptothecin cytotoxicity; camptothecin was equally cytotoxic to both the drug-sensitive parental cell line, KB 3-1, and its multidrug-resistant derivative, KB V1. The ability of camptothecin to overcome MDR1-mediated resistance is most likely due to unimpaired accumulation of camptothecin in MDR1 cells as suggested from the following experiments: (a) cytotoxicity of camptothecin against KB V1 cells was not altered by the known MDR1-reversing agent, verapamil; (b) camptothecin was ineffective as compared with vinblastine in competing with [3H]azidopine for photoaffinity labeling of MDR1; (c) campiothecin was equally efficient in trapping cellular topoisomerase I molecules on chromosomal DNA in the form of cleavable complexes in both KB 3-1 and KB V1 cells. The mechanism by which camptothecin overcomes MDR1-mediated resistance has been further studied using a number of uncharged and charged camptothecin derivatives. In contrast to the uncharged camptothecin derivatives, such as 9-amino-camptothecin and 10,11-methylenedioxy-camptothecin, the charged camptothecin derivative, topotecan, showed reduced cytotoxicity against MDR1-overexpressing KB V1 cells. The reduced cytotoxicity of topotecan in KB V1 cells was due to the overexpression of MDR1 in KB V1 cells since verapamil restored both topotecan accumulation and cytotoxicity. These results suggest that the charge on camptothecin can affect the drug's sensitivity to MDR1. The possible effect of membrane permeability in determining drug selectivity of MDR1 is discussed.

Original languageEnglish
Pages (from-to)6039-6044
Number of pages6
JournalCancer Research
Volume51
Issue number22
Publication statusPublished - Nov 15 1991
Externally publishedYes

Fingerprint

KB Cells
Camptothecin
Carcinoma
Topotecan
irinotecan
Verapamil
Pharmaceutical Preparations
Type I DNA Topoisomerase
Membranes
Vinblastine
Heterografts
Nude Mice

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chen, A. Y., Yu, C., Liu, L-F., Wall, M. E., Wani, M. C., & Liu, L. F. (1991). Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Research, 51(22), 6039-6044.

Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. / Chen, Allan Y.; Yu, Chiang; Liu, Leroy-Fong; Wall, Monroe E.; Wani, Mansukh C.; Liu, Leroy F.

In: Cancer Research, Vol. 51, No. 22, 15.11.1991, p. 6039-6044.

Research output: Contribution to journalArticle

Chen, AY, Yu, C, Liu, L-F, Wall, ME, Wani, MC & Liu, LF 1991, 'Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells', Cancer Research, vol. 51, no. 22, pp. 6039-6044.
Chen AY, Yu C, Liu L-F, Wall ME, Wani MC, Liu LF. Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Research. 1991 Nov 15;51(22):6039-6044.
Chen, Allan Y. ; Yu, Chiang ; Liu, Leroy-Fong ; Wall, Monroe E. ; Wani, Mansukh C. ; Liu, Leroy F. / Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. In: Cancer Research. 1991 ; Vol. 51, No. 22. pp. 6039-6044.
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