This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Seidenfeld, J. Articles by Sprague, W. S. Search for Related Content PubMed PubMed Citation Articles by Seidenfeld, J. Articles by Sprague, W. S.

Comparisons between Sensitive and Resistant Human Tumor Cell Lines Regarding Effects of Polyamine Depletion on Chloroethylnitrosourea Efficacy¹

Department of Pharmacology and the Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611

We have reported that 2-difluoromethylornithine (DFMO)-induced polyamine (PA) depletion sensitized five chloroethylnitrosourea (CENU)-resistant, O⁶-alkylguanine repair-proficient (Mer⁺) human tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), but failed to alter BCNU efficacy in a single CENU-sensitive, repair-deficient (Mer^-) line. Further, alkaline elution assays of DNA interstrand cross-links (ISC) found no BCNU-induced ISC in either PA-depleted or control Mer⁺ cells, suggesting that targets other than ISC may be involved in the DFMO/BCNU drug interaction. To verify that DFMO-induced enhancement of BCNU action segregates with Mer phenotype, we tested three additional Mer^- lines for effects of DFMO pretreatment on BCNU efficacy. We found no potentiation of BCNU by PA depletion in any of our human Mer^- lines. We also used streptozotocin (STZ) to deplete the repair capacity of Mer⁺ cell lines, thus converting their BCNU sensitivity to near that of Mer^- cells. Combined pretreatment with DFMO then STZ did enhance BCNU cell kill relative to STZ pretreatment alone. Exogenous putrescine restored BCNU sensitivity of (DFMO plus STZ)-pretreated cells to that of cells pretreated with STZ alone. Measurements of O⁶-alkylguanine DNA alkyltransferase activity verified that in at least one of the Mer⁺ lines (HT-29), STZ did deplete repair capacity to below detectable limits. These results suggest that in HT-29 cells, STZ and DFMO probably act via differing mechanisms to potentiate BCNU. Our observations also imply that targets for CENUs may differ between Mer⁺ and Mer^- cells, with importance of ISC possibly limited to Mer^- cells. Our data further suggest that PA depletion may potentiate CENUs only at targets critical in Mer⁺ cells. We also noted that 48-h treatments with DFMO markedly reduced clonogenicity of Mer^- cells. Exogenous putrescine restored Mer^- cell survival after DFMO to near that of controls. In contrast, Mer⁺ cells showed little, if any, effect of DFMO treatment on plating efficiency. These results suggest that PA depletion may be cytocidal to some Mer^- cells.

¹ Supported by USPHS Grant CA-44892 from the National Cancer Institute, NIH, Department of Health and Human Services; and by the Northwestern University Cancer Center.

² To whom requests for reprints should be addressed, at Division of Drugs and Toxicology, American Medical Association; 535 North Dearborn Street; Chicago, IL 60610.

Received 6/ 6/89. Revised 10/23/89. Accepted 10/30/89.