Melphalan resistance and photoaffinity labelling of P-glycoprotein in multidrug-resistant Chinese hamster ovary cells

Larrivée, Bruno; Averill, Diana

doi:10.1016/s0006-2952(99)00094-5

Cited by 23 publications

(13 citation statements)

References 44 publications

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“…Additionally, the alkylating agent melphalan has been shown to exhibit additive antiproliferative effects in combination with lonafarnib and is a P-gp substrate [12,29]. Although lonafarnib is a potent P-gp inhibitor and therefore is expected to thwart P-gp-mediated MDR, the compounds cyclophosphamide, 5-FU and cisplatin are not known to be transported by P-gp.…”

Section: Discussionmentioning

confidence: 99%

The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2

Wang¹,

Johnson²

2003

Chemotherapy

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Clinical studies indicate that the farnesyl protein transferase inhibitor SCH66336 (lonafarnib), an anticancer agent developed to antagonize oncogenic Ras, is generally well tolerated. Lonafarnib has also demonstrated therapeutic synergy with coadministered taxanes, vincristine, cisplatin, cyclophosphamide, 5-fluorouracil (5-FU) and Gleevec. Lonafarnib has recently been shown, in addition, to be a potent inhibitor of the transmembrane efflux transporter P-glycoprotein (P-gp), which confers cellular resistance to the substrates vincristine, taxol and paclitaxel. Treatment with lonafarnib would therefore be predicted to be synergistic with these coadministered cancer therapeutics that are substrates of P-gp. However, cisplatin, 5-FU and cyclophosphamide are not P-gp substrates, yet cisplatin, 5-FU and possibly cyclophosphamide are purported substrates for multidrug resistance proteins (MRPs) 1 and 2 (known to cause chemotherapy resistance). Lonafarnib is shown here to inhibit the function of MRP1 and MRP2 with a potency similar to that of cyclosporin A and may therefore cause the observed synergy with cisplatin and other agents by inhibiting these MRPs. Coadministration of lonafarnib could thus reduce chemotherapy dosage and hence produce lower exposure to normal cells and less undesired toxicity.

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Section: Discussionmentioning

confidence: 99%

The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2

Wang¹,

Johnson²

2003

Chemotherapy

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“…Bamdad et al (1999) have suggested that the accumulation of adriamycin, rhodamine-123, benzo(a)pyrene and 7,12-dimetylobenzoanthracene in ciliate cells, Tetrahymena pyriformis, is significantly enhanced in the presence of ciclosporin. Larrive´e & Averill (1999) have proved that ciclosporin can increase the intracellular accumulation of melphalan in Chinese hamster ovary cells.…”

Section: Mdr Reversing By Pharmacological Modulationmentioning

confidence: 98%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

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It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

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“…C shows that β‐NTP/Pi of the tumor increases from about 0.4 to 0.6 after 3 h at 26 mM blood glucose. There is substantial evidence that LPAM activity is subject to multidrug resistance, an energy‐driven process associated with the formation of glutathione conjugates with this agent . This could account for the increased resistance of DB‐1 melanomas to LPAM under hyperglycemic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…2C shows that β-NTP/Pi of the tumor increases from about 0.4 to 0.6 after 3 h at 26 mM blood glucose. There is substantial evidence that LPAM activity is subject to multidrug resistance, an energy-driven process associated with the formation of glutathione conjugates with this agent (30)(31)(32). This could account for the increased resistance of DB-1 melanomas to LPAM under and surgically exposed liver (n = 3) (C), and extracellular pH (pH e ) profile as a function of time of surgically exposed liver (n = 3) (D) and skeletal muscle (n = 3) (E), in response to lonidamine (LND; 100 mg/kg, intraperitoneally) administration at time zero, 20 min after an intravenous infusion of glucose (26 mM) (filled squares).…”

Section: Discussionmentioning

confidence: 99%

Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan

et al. 2015

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We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for selective intracellular acidification of cancer cells and for potentiating the activity of N-mustard antineoplastic agents. We performed this study to evaluate whether induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; i.p.) on inducing intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi), extracellular pH (pHe) and bioenergetics (βNTP/Pi) were reduced by 0.7 units (p<0.001), 0.3 units (p>0.05) and 51.4% (p<0.05), respectively. Therapeutic response to LPAM (7.5 mg/kg; i.v.) + LND (100 mg/kg; i.p.) was reduced by about a factor of 3 under hyperglycemic conditions compared to normoglycemia, producing a growth delay of 7.76 d (tumor doubling time = 5.31 d, cell kill = 64%) compared to LND alone of 1.70 d and LPAM alone of 0.29 d. Under normoglycemic conditions LND plus LPAM produced a growth delay of 17.75 d, corresponding to a cell kill of 90 % at the same doses for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of ~6 (p<0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor most likely because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that addition of glucose during treatment with LND diminishes the activity of this agent.

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Melphalan resistance and photoaffinity labelling of P-glycoprotein in multidrug-resistant Chinese hamster ovary cells

Cited by 23 publications

References 44 publications

The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2

The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Effects of hyperglycemia on lonidamine‐induced acidification and de‐energization of human melanoma xenografts and sensitization to melphalan

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