Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance (MDR) in a variety of human tumors such as renal cell carcinoma (RCC) is thought to be caused by expression of the mdr1 gene and may be reversed by applying chemosensitizers such as Dexverapamil that inhibit the mdr1 gene product P-glycoprotein. On the basis of our preclinical analysis, we initiated a clinical (GCP) study with vinblastine (VBL), the most effective--if at all--chemotherapeutic agent; dexverapamil; and dexamethasone in patients with RCC. All patients had histologically proven RCC that was metastatic and progressive at study entry. The statistical design featured a preliminary study of two cycles of VBL alone followed by tumor evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for a minimum of three cycles of combination therapy. Having obtained institutional permission by the ethical review committee (MEC 124, 106-1993/12), we enrolled 24 patients on this protocol starting on May 3, 1993. In the preliminary study, 1 complete response (CR) was achieved with VBL alone, and myelotoxicity led to an adequate dose reduction from 2 mg/m2 VBL per day given as a 5-day continuous infusion (days 1-5) in 6/10 yet evaluable patients to 1.4 mg/m2 per day. In 8/11 yet evaluable patients, dexverapamil doses reached > or = 3000 mg/day by 7-day oral uptake (days 0-6, supported by 20 mg dexamethasone given twice daily), which is significantly higher than those previously reported. The combination of VBL given at 1.4 mg/m2 per day plus, dexverapamil given at 3000 mg per day was felt to be safe and well tolerated. Nine patients were yet evaluable for response. One partial response and three minor responses were noted in this heavily pretreated study population. It appears that this innovative approach may have some activity in RCC and may eventually lead to a rational treatment modality. Careful evaluation in ongoing studies is warranted.
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PMID:Chemoresistance of renal cell carcinoma: 1986-1994. 782 Jan 44

Two cell lines, SNK57 and NKB1, were established from human bladder cancer: SNK57 from a transitional cell carcinoma (TCC) in a 73-year-old female and NKB1 from a residual TCC following MEC (methotrexate, farmorubicin and cisplatin) chemotherapy in a 64-year-old female. Doubling time of SNK57 and NKB1 cells was 24 hours and 45 hours, respectively. The chromosome number of both cell lines was 100 percent anueploid with a mode of 43 chromosomes for SNK57 and 107 for NKK1. Both SNK57 and NKK1 induced tumors at the site of subcutaneous injection of nude mice. Histology of the tumors closely resembled that of the original ones from which they were derived. Although NKB1 was 4 times more resistant to doxorubicin (ADM) as compared to SNK57, overexpression of MDR1 gene product, P-glycoprotein was not evident in NKB1 as well as SNK57. These two new cell lines with different chemosensitivity to ADM may be a useful model for developing new chemotherapeutic strategies for human bladder cancer.
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PMID:Establishment and characterization of two human bladder cancer cell lines. 918 30

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P <.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.
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PMID:Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspodar). 992 Aug 27

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr 1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24 h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.
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PMID:Treatment of poor prognosis AML patients using PSC833 (valspodar) plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). 1050 Jul 79

Fludarabine (flu) -containing regimens such as flu, cyclophosphamide and rituximab have been established as one of the standard first line therapy in medically-fit chronic lymphocytic leukemia (CLL) patients. Therefore, flu-refractory (primary flu-insensitivity or flu-caused relapse) remains a major problem causing treatment failure for CLL patients. We isolated the peripheral blood mononuclear cells (PBMCs) from CLL patients and treated with flu to find flu-refractory cases, and established flu-resistant clonal cells to study molecular mechanism of flu-resistance. By comparing parental MEC-2 cells, a human CLL cell line, we found that flu-resistant clonal cells were significantly increased lethal dose 50 of flu concentration, and up-regulated expression of P-glycoprotein, a drug-resistant marker, glucosylceramide synthase (GCS), an enzyme that can convert ceramide to glucosylceramide, and CD34, a leukemia stem cell marker. Overexpression of GCS leads to promptly elimination of cellular ceramide levels and accumulation of glucosylceramide, which reduces apoptosis and promotes survival and proliferation of flu-resistant clonal cells. Furthermore, we demonstrated that the accumulation of glucosylceramide can be blocked by PDMP to restore flu-sensitivity in flu-resistant clonal cells. We also found that elevating glucosylceramide levels in flu-resistant clonal cells was associated with up-regulation of GCS and CD34 expression. Importantly, overexpression of GCS or CD34 was also determined in flu-refractory PBMCs. Our results show that flu-resistance is associated with the alteration of ceramide metabolism and the development of leukemia stem cell-like cells. The flu-resistance can be reversed by GCS inhibition as a novel strategy for overcoming drug resistance.
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PMID:Fludarabine-resistance associates with ceramide metabolism and leukemia stem cell development in chronic lymphocytic leukemia. 3023 56