Non-chemotherapeutic agents that potentiate chemotherapy efficacy

Stewart, David J.; Evans, William K.

doi:10.1016/0305-7372(89)90002-9

Cited by 57 publications

(27 citation statements)

References 169 publications

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Section: Resultsmentioning

confidence: 99%

“…The mechanism by which this ogcurs is not known but is thought to be related to P-glycoprotein antagonism (Stewart and Evans, 1989). It has been suggested previously that calcium channel blockers may reverse non-MDR-associated resistance via their effects on tumour blood flow (Stewart and Evans, 1989). Our results clearly demonstrate, however, that modification of drug toxicity in this model system by flunarizine is not related to an increase in blood flow, since the increase in blood flow observed at the 4 mg kg1' flunarizin dose was not associated with any change in tumour growth delay as compared with melphalan alone.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, methods that increase drug uptake within tumour might increase the therapeutic efficacy of melphalan in the resistant line. It has been suggested that reversal of alkylator drug resistance by calcium channel blockers may be due to an increase in drug delivery as a consequence of improved blood flow (Stewart and Evans, 1989).…”

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confidence: 99%

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Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Castellino

Friedman²,

Elion³

et al. 1995

Br J Cancer

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Summanr Flunarizine. a diphenylpiperazine calcium channel blocker. is known to increase tumour blood flow. It also interferes with calmodulin function. repair of DNA damage and drug resistance associated with P-glvcoprotein. Flunarizine was tested for its ability to modulate either cyclophosphamide-or melphalaninduced growth delay for a drug-resistant rhabdomyosarcoma xenograft (TE-671 MR) and the drug-sensitive parent line (TE-671). in which P-glycoprotein is not involved in the mechanism of drug resistance. Tumour blood flow was increased by 30% after a flunarizine dose of 4 mg kg-'. but no modification in growth delay was induced by melphalan (12 mg kg-'). In contrast. a 60 mg kg-' dose of flunarizine had no effect on tumour blood flow. but the same dose created significant enhancement in melphalan-induced tumour regrowth delay in both tumour lines. The dose-modifying factor for flunarizine as an adjuvant to melphalan was approximately 2 for both tumour lines. Although blood flow measurements were not performed with the combination of flunarizine and melphalan, the results from flunarizine alone suggested that augmentation of melphalan cytotoxicity is not mediated by changes in blood flow. In contrast. flunarizine did not affect drug sensitivity to cyclophosphamide in groups of animals bearing the drug-sensitive parent tumour line. These results suggest that the mechanism of drug sensitivity modification by flunarizine is not related to modification of tumour blood flow, but may be mediated by modification of transport mechanisms that are differentially responsible for cellular uptake and retention of melphalan as compared With cyclophosphamide.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Castellino

Friedman²,

Elion³

et al. 1995

Br J Cancer

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“…[34][35][36]. The rapidly increasing list of so-called chcmosensitizers (CS) includes cal cium channel blockers such as verapamil, cyclic peptide anti biotics such as cyclosporin A, antiarrhythmic agents such as amiodarone, calmodulin inhibitors such as trifluoperazine, antimalarials such as quinine and quinidine, antiestrogens such as tamoxifen und toremifene, and steroid hormones such as progesterone (table 1).…”

Section: Experim Ental Mdr1 Reversalmentioning

confidence: 99%

Reversal of P-Glycoprotein-Associated Multidrug Resistance: From Bench to Bedside

Lehnert¹

1994

Oncol Res Treat

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Reversal of P-glycoprotein-associated multidrug resistance (MDR1) has received much attention in recent years. A number of agents has been identified which are capable of overcoming MDR1 in experimental tumor models. The clinical effec- tiveness of such chemosensitizers (CS) has been limited to date. Nonetheless, there are data suggesting that the concept of MDR1 reversal might also function in cancer patients. It always has been a concern that inhibition of physiological P-glycoprotein function may increase chemotherapy toxicity. Recent data suggest that CS can inhibit biliary and/or renal elimination of cytotoxic agents, resulting in increased bone marrow toxicity. It seems likely that such phenomena will be more frequently observed in the future as more potent CS become available. In order to making progress in this field, future clinical studies of CS must strictly adhere to the usual standards of clinical drug development, i.e., starting with phase I and pharmacokine-tic studies and only based on these results proceeding to activity studies (phases II and III). Clinical MDR1 reversal is a complex task, and it is only through carefully conducted trials that significant progress in this area may be possible. For the time being, the clinical use of CS continues to be an experimental approach and thus should not be pursued outside the context of controlled studies.

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“…, den Glutathionmetabolismus [1,8], die Topoisomeraseenzyme [4,7] und weitere wie z. B. das Multi drug-resistance-associated-Protein (MRP) [2].…”

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Multidrug Resistance

Mickisch¹

1996

Urologe A

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The past decade has seen the successful application of genetic techniques in the dissection of the most important phenotypes of cancer cells. In the case of drug resistance mechanisms, the elucidation of the genes involved in resistance to anticancer agents has led to new and unexpected information about tumor physiology and may well open therapeutic options by virtue of reversing clinical chemoresistance. The experimental characterization of defined multidrug resistance factors, such as P-glycoprotein, multidrug resistance associated protein, topoisomerase, or glutathione-S-transferase in urologic malignancies, is now relatively comprehensive, allowing for an initial analysis. Clinical studies on some of these concepts have been started and will be the subject of careful scrutiny. We expect that they will have a considerable impact on the way certain urologic anticancer strategies will be pursued in the future.

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Non-chemotherapeutic agents that potentiate chemotherapy efficacy

Cited by 57 publications

References 169 publications

Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Flunarizine enhancement of melphalan activity against drug-sensitive/resistant rhabdomyosarcoma

Reversal of P-Glycoprotein-Associated Multidrug Resistance: From Bench to Bedside

Multidrug Resistance

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