DNA repair enzyme expression in chronic lymphocytic leukemia vis-à-vis nitrogen mustard drug resistance.
Nitrogen mustard resistance in B-cell chronic lymphocytic leukemia (B-CLL) has been associated with enhanced DNA repair and increased expression of DNA repair enzymes. Lymphocytes from patients with nitrogen mustard resistant B-CLL displayed a fivefold increase in resistance to melphalan in vitro as compared to those from untreated patients concordant with our definition of clinical resistance. We have performed Northern analysis using a cohort consisting of 11 untreated and 12 treated-resistant patients. Increased expression of ERCC-1 was not found to be associated with nitrogen mustard resistance, nor did we find altered expression of the DNA repair enzymes: ERCC-2, DNA polymerase beta, or topoisomerase I. There was also no difference in the levels of ERCC-1 protein between melphalan sensitive and resistant B-CLL lymphocytes. Analysis of genes involved in nitrogen mustard detoxification revealed that metallothionein was weakly expressed, while transcripts encoding glutathione-S-transferase alpha were undetectable. Thus, it is unlikely either of these proteins plays a role in the resistance. The results of the cytotoxicity assay validate the use of B-CLL as a model to study nitrogen mustard resistance. This model allows us to perform in vitro studies using a tumor which develops resistance in vivo. The results of this study suggest that nucleotide excision repair, as represented by ERCC-1 and ERCC-2, is not the limiting step in B-CLL nitrogen mustard resistance.
Bramson
J
J
Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
McQuillan
A
A
Panasci
L C
LC
D000368:Aged; D000369:Aged, 80 and over; D004265:DNA Helicases / Q000096:biosynthesis; D011088:DNA Ligases / Q000096:biosynthesis*; D004256:DNA Polymerase I / Q000096:biosynthesis; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D004351:Drug Resistance / Q000502:physiology; D004720:Endonucleases; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology*; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds / Q000378:metabolism / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051759:Xeroderma Pigmentosum Group D Protein
D004268:DNA-Binding Proteins; D009588:Nitrogen Mustard Compounds; D011506:Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D004256:DNA Polymerase I; C071447:ERCC1 protein, human; D004720:Endonucleases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D004264:DNA Topoisomerases, Type I; D011088:DNA Ligases; D008558:Melphalan