P-glycoprotein is a product of the multidrug resistance (MDR1) gene, which is a major cause of the refractoriness of malignant lymphomas to conventional chemotherapeutic regimens containing anthracycline. l-asparaginase-containing regimens such as SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) are effective for ENKL.
The aim of our study was to establish a lymphoma, cellular system where a de novo acquisition of multidrug resistance is specifically related to overexpression of a transgenic, human MDR1.
Apoptosis induction and the interaction between epirubicin and the silicon-substituted compounds were studied in human MDR-1 gene-transfected mouse lymphoma and its parent cell line, Colo320/MDR-LRP and sensitive subline Colo205, by means of rhodamine 123 accumulation.
Neither codeinone nor morphine inhibited P-glycoprotein-mediated rhodamine-123 efflux in multidrug resistant mouse T lymphoma L5178 transfected with human MDR 1 gene.
When coupled with an anti-CD19 targeted antibody, this formulation was also effective at delivering an MDR1 asODN to a multidrug-resistant human B-lymphoma cell line in vitro, decreasing the activity of P-glycoprotein.
Through use of oligonucleotide hybridization, the genomic content and expression of individual MDR-1 alleles were examined in normal tissues, unselected and drug selected cell lines, and malignant lymphomas.
MDR1 has been the most studied in hematological malignancies, particularly in lymphoma and multiple myeloma (MM), diseases generally considered as overexpressing such mechanisms in relapse.
The preponderance of evidence suggests that mdr1 expression is relatively low in untreated patients (10% to 20% of lymphomas positive), but increases in patients with recurrent disease (50% to 70% positive).
These results indicate that expression of the mdr1 gene is not always detectable in cases of malignant lymphoma resistant to chemotherapy, but the detectable expression of mdr1 gene may predict clinical resistance to chemotherapy.
MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma.