Of resistant MM cell lines growing GSH soon after L-PAM remedy.56 Remedy with thiols (NAC

Of resistant MM cell lines growing GSH soon after L-PAM remedy.56 Remedy with thiols (NAC and STS) antagonized the cytotoxic synergy of BSO L-PAM, mimicking the effect of GSH as previously reported.43,57 The effect of NAC is independent of GSH due to the fact in the presence of BSO L-PAM, NAC didn’t improve GSH FAAH Accession levels. In addition, as non-thiol antioxidants (vitamins C and E) did not antagonize BSO L-PAM cytotoxicity, it’s most likely that NAC and STS act to straight replace GSH as an absorbent on the highly reactive L-PAM. In conclusion, our study demonstrated that depletion of GSH by BSO significantly enhanced the activity of L-PAM against MM in vitro and in vivo. A recently completed NANT phase I study demonstrated that myeloablative BSO L-PAM was well tolerated in neuroblastoma patients. Taken collectively, these information help the development of a phase I clinical trial of BSO myeloablative dosing of L-PAM and stem cell support in sufferers with relapsed and refractory MM. CONFLICT OF INTERESTThe authors declare no conflict of interest. 8 Bellamy WT, Dalton WS, Gleason MC, Grogan TM, Trent JM. Development and characterization of a melphalan-resistant human multiple myeloma cell line. Cancer Res 1991; 51: 995002. 9 Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents made use of within the treatment of haematological malignancies. Blood Rev 1992; six: 16373. 10 Mulcahy RT, Bailey HH, Gipp JJ. c-Myc Synonyms Up-regulation of gamma-glutamylcysteine synthetase activity in melphalan-resistant human numerous myeloma cells expressing increased glutathione levels. Cancer Chemother Pharmacol 1994; 34: 671. 11 Mulcahy RT, Bailey HH, Gipp JJ. Transfection of complementary DNAs for the heavy and light subunits of human gamma-glutamylcysteine synthetase outcomes in an elevation of intracellular glutathione and resistance to melphalan. Cancer Res 1995; 55: 4771775. 12 Bailey HH. L-S, R-buthionine sulfoximine: historical development and clinical issues. Chem Biol Interact 1998; 11112: 23954. 13 Dimopoulos MA, Souliotis VL, Anagnostopoulos A, Bamia C, Pouli A, Baltadakis I et al. Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in a number of myeloma. Haematologica 2007; 92: 1505512. 14 Griffith OW, Meister A. Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem 1979; 254: 7558560. 15 Griffith OW. Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesis. J Biol Chem 1982; 257: 137043712. 16 O’Dwyer PJ, Hamilton TC, LaCreta FP, Gallo JM, Kilpatrick D, Halbherr T et al. Phase I trial of buthionine sulfoximine in mixture with melphalan in sufferers with cancer. J Clin Oncol 1996; 14: 24956. 17 Dorr RT, Liddil JD, Soble MJ. Cytotoxic effects of glutathione synthesis inhibition by L-buthionine-(SR)-sulfoximine on human and murine tumor cells. Invest New Drugs 1986; 4: 30513. 18 Bailey HH, Mulcahy RT, Tutsch KD, Arzoomanian RZ, Alberti D, Tombes MB et al. Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an try at modulation of glutathione. J Clin Oncol 1994; 12: 19405. 19 Anderson CP, Tsai JM, Meek WE, Liu RM, Tang Y, Forman HJ et al. Depletion of glutathione by buthionine sulfoxine is cytotoxic for human neuroblastoma cell lines by means of apoptosis. Exp Cell Res 1999; 246: 18392. 20 Anderson CP, Reynolds CP. Synergistic cytotoxicity of buthionine sul.