1986
DOI: 10.1172/jci112450
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Cyclosporin A reverses vincristine and daunorubicin resistance in acute lymphatic leukemia in vitro.

Abstract: MethodsThe development of drug resistance by tumor cells is a major obstacle to the cure of human malignancy. Cyclosporin A (CsA) completely reverses primary resistance to vincristine and cross resistance to daunorubicin in a pleiotropic drug-resistant subline of human T cell acute lymphatic leukemia. This subline is over 50-fold resistant to vincristine and fivefold resistant to daunorubicin. CsA has little effect on vincristine or daunorubicin activity in drug-sensitive parental leukemia and corrects daunoru… Show more

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Cited by 295 publications
(109 citation statements)
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“…The higher brain levels of vinblastine in the mdr1a knockout mouse suggests that blocking Pgp with a modulating agent such as CsA would result in higher CNS and CSF concentrations of drugs that are Pgp substrates. In our non-human primate model, we achieved CsA blood levels that exceeded concentrations required to inhibit Pgp in vitro [12,13,24] and resulted in altered doxorubicin pharmacokinetics (42% reduction in doxorubicin clearance) in the animals. However, CsA did not signi®cantly increase the CSF penetration of doxorubicin.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…The higher brain levels of vinblastine in the mdr1a knockout mouse suggests that blocking Pgp with a modulating agent such as CsA would result in higher CNS and CSF concentrations of drugs that are Pgp substrates. In our non-human primate model, we achieved CsA blood levels that exceeded concentrations required to inhibit Pgp in vitro [12,13,24] and resulted in altered doxorubicin pharmacokinetics (42% reduction in doxorubicin clearance) in the animals. However, CsA did not signi®cantly increase the CSF penetration of doxorubicin.…”
Section: Discussionmentioning
confidence: 99%
“…Cyclosporin A (CsA) is a potent chemosensitizing agent. CsA concentrations of 1 to 5 lg/ml modulate Pgp in vitro [12,13], and clinical trials utilizing CsA in combination with chemotherapy have been performed [14±17]. In animal models and in the clinical trials, Pgp modulation with CsA decreases the clearance of anticancer drugs that are Pgp substrates and enhances their toxicity, presumably by inhibition of Pgp-dependent drug elimination pathways in normal liver [18].…”
Section: Introductionmentioning
confidence: 99%
“…However, Kessel & Corbett (1985) were unable to demonstrate a correlation between adriamycin uptake and adriamycin resistance in murine solid tumours rendered resistant to adriamycin by in vivo drug exposure. We were similarly unable to detect significant differences in daunorubicin uptake between our daunorubicin-sensitive and daunorubicin-resistant Ehrlich ascites carcinoma subline and drug sensitive versus pleiotropic drug resistant human acute lymphatic leukaemia subline (Slater et al, 1986), suggesting that the mechanism of CsA effect lies beyond the modification of drug transport. Since the acquisition of equimolar concentrations of anthracyclines by anthracycline resistant compared to anthracycline sensitive tumour cells fails to restore equivalent cytotoxic drug effect to these cells (Kessel & Wilberding, 1985b;Sikic et al, 1985), the mechanism by which calcium channel blocking agents and calmodulin inhibitors restore drug sensitivity must extend beyond drug retention.…”
Section: Daunorubicin Inhibition Of [3h]-thymidine Incorporationmentioning
confidence: 59%
“…Although the efficacy of CsA in reversing drug resistance of human tumours in vivo has not yet been demonstrated, we do note important in vitro activity of CsA in daunorubicin resistant human acute lymphatic leukaemia. CsA completely reverses 50-fold primary resistance to vincristine and 5-fold cross resistance to daunorubicin in a pleiotropic drug resistant subline of GM3639 human T cell acute lymphatic leukaemiaHuman Genetic Mutant Cell Repository, Camden, New Jersey (Slater et al, 1986).…”
Section: Daunorubicin Inhibition Of [3h]-thymidine Incorporationmentioning
confidence: 99%
“…In contrast to these data. McLachlan et al (1991) Following a description of its ability to act as a modifier of multidrug resistance (Slater et al, 1986: Twentyman et al. 1987 CsA was shown to bind to P-glycoprotein.…”
Section: Discussionmentioning
confidence: 99%