MDR-1 gene expression, anthracycline retention and cytotoxicity in human lung-tumor cells from refractory patients.
Lung-tumor cells from pleural effusion of four refractory patients and in cell lines established from them were analyzed for anthracycline retention, cytotoxicity, and MDR-1 gene and P-glycoprotein expression. Murine leukemic P388 and doxorubicin-resistant P388/R84 lines were used as controls. The 50% growth-inhibitory concentration (IC50) for doxorubicin among lung-tumor lines varied from 0.16 to 0.31 microM in soft agar. Heterogeneity in doxorubicin or daunorubicin retention and response to the efflux-blocking action of 25 microM prochlorperazine was noted in pleural effusion of FCCL-1, -4, and -8. Among the cell lines established, an efflux-blocking effect in a subpopulation was noticed only in FCCL-1 and -4. Although the MDR-1 gene was present in all cell lines, including P388, its expression was pronounced only in P388/R84 and FCCL-1. In situ hybridization of antisense RNA probe to tumor cells showed high heterogeneity for MDR-1 message in the human lung-tumor cells as compared with the murine cells. Northern and slot blot hybridization confirmed in situ hybridization in lines with high levels of MDR-1 expression. The synthesis of MDR-1 mRNA and P-glycoprotein in tumor lines was correlated. The results suggest that because of extensive tumor-cell heterogeneity in human tumors, monitoring of MDR expression by in situ hybridization, quantitation of P-glycoprotein content by laser flow cytometry (and/or immunohistochemical methods), and drug efflux (by laser flow cytometry) may be the best ways to monitor multidrug resistance in human tumors.
Ramachandran
C
C
Department of Radiation Oncology, University of Miami Medical School, FL 33101.
Sauerteig
A
A
Sridhar
K S
KS
Thurer
R J
RJ
Krishan
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004317:Doxorubicin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007941:Leukemia P388 / Q000235:genetics; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004317:Doxorubicin