Modulation of multidrug-resistant multiple myeloma by cyclosporin

Sonneveld, Pieter; Löwenberg, Bob; Durie, BG; Lokhorst, Henk M.; Jp, Marie; Zittoun, R; Solbu, G.; Suciu, Stefan; Nooter, Kees

doi:10.1016/0140-6736(92)92353-h

Cited by 299 publications

(107 citation statements)

References 19 publications

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“…Immunocytochemical detection of P-gp and MRP was performed according to previously used procedures (Sonneveld et al, 1992;Nooter et al, 1995). Cytospin preparations were fixed in cold acetone (10 min, 0C), air dried and incubated with the MRPspecific MAb MRPrl or with the P-gp-specific MAb C219.…”

Section: P-gp and Mrp Expressionmentioning

confidence: 99%

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

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Summary In order to unravel possible mechanisms of clinical resistance to topoisomerase inhibitors, we developed a topotecan-resistant human IGROV-1 ovarian cancer cell line, denoted IGROVTlOOr, by stepwise increased exposure to topotecan (TPT). The IGROVT100r cell line was 29-fold resistant to TPT and strongly cross-resistant to . However, the IGROVTlOOr showed only threefold resistance to camptothecin (CPT). Remarkably, this cell line was 32-fold resistant to mitoxantrone, whereas no significant cross-resistance against other cytostatic drugs was observed. No differences in topoisomerase protein levels and catalytic activity as well as topoisomerase cleavable complex stabilization by CPT in the IGROV-1 and IGROVTIOOr cell lines were observed, indicating that resistance in the IGROVTlOOr cell line was not related to topoisomerase I-related changes. However, resistance in the resistant IGROVTlOOr cell line to accompanied by decreased accumulation of the drugs to approximately 15% and 36% of that obtained in IGROV-1 respectively. No reduced accumulation was observed for CPT. Notably, accumulation of TPT in the IGROV-1 cell line decreased under energy-deprived conditions, whereas the accumulation in the IGROVTlOOr cell line increased under these energy-deprived conditions. The efflux of TPT at 370C was very rapid in the IGROV-1 as well as the IGROVT100r cell line, resulting in 90% efflux within 20 min. Importantly, the efflux rates of TPT in the IGROV-1 and IGROVTlOOr cell lines were not significantly different and were shown to be independent on P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP). These results strongly suggest that the resistance of the IGROVTlOOr cell line to TPT and SN-38 is mainly caused by reduced accumulation. The reduced accumulation appears to be mediated by a novel mechanism, probably related to impaired energy-dependent uptake of these topoisomerase drugs.

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Section: P-gp and Mrp Expressionmentioning

confidence: 99%

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Maliepaard²,

Nooter³

et al. 1998

Br J Cancer

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“…Cyclosporine is another MDR modulator that has been used together with the VAD regimen. However, its addition to chemotherapy resulted in a high incidence of neurotoxicity and myelosuppression (Sonneveld et al, 1992b). PSC 833, an analogue of Cyclosporine D, appears to have a high binding affinity to P-glycoprotein but to be less toxic (Jonsson et al, 1992;Sonneveld et al, 1992a).…”

Section: Overcoming Drug Resistance In Multiple Myelomamentioning

confidence: 99%

An update on molecular biology and drug resistance mechanisms of multiple myeloma

Mutlu

Kiraz

Gündüz

et al. 2015

Critical Reviews in Oncology/Hematology

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Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. © 2015 Elsevier Ireland Ltd

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“…[20][21][22][23][24][25][26][27] The percentage of patients with P-gp overexpression at primary diagnosis ranged between 0 and 41%. [20][21][22][23] The percentage of Pgp-positive patients at relapse or progression ranged between 29 and 59%. 24,25 In our study 32% of the patients at primary diagnosis ( Table 1) and 33% of patients at relapse or progression were P-gp positive (Table 2).…”

Section: P170-glycoproteinmentioning

confidence: 99%

“…The assumption that P-gp might be a crucial resistance mechanism was based upon early reports 20,28,29 and reactivated by the fact that prior exposure to vincristine and doxorubicin induces an increase in P-gp expression in human plasma cell myelomas. 22 Additionally, Sonneveld et al 21 demonstrated that cyclosporine, a so-called modulator of P-gp, has the potency to overcome chemotherapy refractoriness in MM patients. However, no relationship between P-gp expression and response to VAD treatment 24,30 and no benefit from the modulator verapamil could be shown in larger trials.…”

Section: P170-glycoproteinmentioning

confidence: 99%

Cellular resistance mechanisms with impact on the therapy of multiple myeloma

Gieseler

Nüssler²

1998

Leukemia

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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.

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Modulation of multidrug-resistant multiple myeloma by cyclosporin

Cited by 299 publications

References 19 publications

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

Reduced cellular accumulation of topotecan: a novel mechanism of resistance in a human ovarian cancer cell line

An update on molecular biology and drug resistance mechanisms of multiple myeloma

Cellular resistance mechanisms with impact on the therapy of multiple myeloma

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