Cellular resistance mechanisms with impact on the therapy of multiple myeloma

Abstract

Multiple myeloma (MM) is characterized by bone marrow infiltration with abnormal plasma cells which synthesize monoclonal immunoglobulins (Ig) or Ig fragments. Regularly, MM cells exhibit a high intrinsic resistance to available chemotherapeutic strategies. A number of cellular alterations including the cellular membrane, such as mutations of the glucocorticoid receptor or expression of membrane transport proteins, detoxification mechanisms and altered expression of topoisomerases, have been described. In addition to anti-apoptotic survival mechanisms, involving abnormalities of several oncogenes and suppressor genes (ras, c-myc, p53, Rh and bcl-2), the broad resistance spectrum might be explained but clinical studies which include the evaluation of resistance factors are missing. On the other hand, risk factor evaluation is important as a number of therapeutical strategies with different intensities from corticosteroid monotherapy up to high-dose chemotherapy with tandem autologous bone marrow transplantation exist.

Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914)

“…Obviously, MDR 1 is only one of several mechanisms through which myeloma patients may become refractory to chemotherapy (Gieseler & Nussler, 1998;Raaijmakers et al, 1998;Sonneveld, 1999). The question remains whether a benefit by MDR 1 reversal may be expected early during the disease, when the frequency of MDR 1 and other resistance pathways may still be low, as opposed to highly refractory patients who have no other treatment options left (Futscher et al, 1996;Pilarski et al, 1998).…”

A Molecular Basis for Damage Recognition in Eukaryotic Nucleotide Excision Repair

“…Searching from the opposite direction, Rosenblum et al (1995) found that melanoma cells (A375‐M) that were made resistant for the IT ZME‐gelonin (also type I), by incubating with the IT, also became resistant for the cytostatics vincristine and doxorubicin. If all findings are taken together, the conclusion may be that (type I) IT resistance is not directly related to P‐gp but to other, currently unknown, mechanisms that are co‐selected with development of resistance (Gieseler and Nubler, 1998).…”

Correlation of rhodamine 123 efflux by neoplastic plasma cells with clinical and biological characteristics of multiple myeloma

“…Several reports have suggested that MDR1 expression is an independent prognostic factor associated with a poor outcome in acute myeloid leukemia, non-HodgkinЈs lymphoma, and acute lymphoblastic leukemia (16). In MM, a careful analysis of the literature shows the existence of disturbing discrepancies in the incidence of MDR1 overexpression, ranging from 0% to 41% of cases (17)(18)(19)(20)(21). Such a variability has been related, at least in part, to technical questions.…”

“…However, different clones have been employed (18,20). In other reports, functional assays have been used in which either the doxorubicin or the rhodamine 123 efflux were measured (17,22). An additional factor that may contribute to discrepant results is that MDR1 expression is measured on total BM cells and not specifically on PC.…”

“…Although several studies have suggested the existence of a relationship between the MDR1 phenotype and low response rates to doxorubicin/vincristine/dexamethasone (VAD) (19)(20)(21), these findings could not be confirmed by other groups (4). In a similar way, conflicting results have been reported regarding the independent prognostic value of MDR1 expression (17,18,22).…”