Abstract
SDZ PSC 833 (PSC 833) is a cyclosporin A analogue that is under clinical investigation in combination with doxorubicin (Dx) or other anticancer agents as a type-1 multidrug resistance (MDR-1)-reversing agent. The present study was focused on the effects of PSC 833 on the distribution and toxicity of Dx in non-tumor-bearing CDF1 male mice. Mice were given PSC 833 i.p. at 30 min before i.v. Dx treatment. Dx levels were determined by a high-performance liquid chromatography (HPLC) assay at different times during a 72-h period following Dx treatment in the serum, heart, intestine, liver, kidney, and adrenals of mice. In all tissues, Dx area under the concentrationtime curve (AUC) values were much greater in mice receiving 10 mg/kg Dx in combination with 12.5 or 25 mg/kg PSC 833 than in mice receiving Dx alone. The highest increase in Dx concentrations was found in the intestine, liver, kidney, and adrenals. Lower, albeit significant, differences were found in the heart. PSC 833 did not appear to influence either urinary or fecal Dx elimination or Dx metabolism to a great extent. Doses of PSC 833 devoid of any toxicity potentiated the acute and delayed toxicity of Dx dramatically. The mechanism responsible for this enhanced toxicity has not yet been elucidated but is likely to be related to an increased tissue retention of Dx due to inhibition of the P-glycoprotein (Pgp) pump by PSC 833, as has recently been proposed for cyclosporin A.
Similar content being viewed by others
Abbreviations
- MDR :
-
Multidrug resistance
- mdr-1 gene :
-
multidrug resistance-1 gene
- Pgp :
-
P-glycoprotein
- PSC 833 :
-
SDZ PSC 833
- Dx :
-
doxorubicin
- HPLC :
-
high-performance liquid chromatography
- AUC :
-
area under the concentration-time curve
References
Bartlett NL, Lum BL, Fisher GA, Brophy NA, Ehsan MN, Halsey J, Sikic BI (1994) Phase I trial of doxorubicin with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 4:835
Bates SE (1993) Clinical reversal of multidrug resistance. Proc Am Assoc Cancer Res 34:568
Boesch D, Loor F (1994) Extent and persistence of P-glyco-protein inhibition in multidrug-resistant P388 cells after exposure to resistance-modifying agents. Anticancer Drugs 5: 229
Boesch D, Gaveriaux C, Jachez B, Pourtier-Manzanedo A, Bollinger P, Loor F (1991) In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res 51:4226
Boesch D, Muller K, Pourtier-Manzanedo A, Loor F (1991) Restoration of daunomycin retention in multidrug-resistant P388 cells by submicromolar concentrations of SDZ PSC 833, a nonimmunosuppressive cyclosporin derivative. Exp Cell Res 196: 26
Boote DJ, Dennis IF, Twentyman PR, Osborne RJ, Laburte C, Hensel S, Bleehen NM (1994) A phase I study of intravenous SDZ PSC-833 in combination with etoposide in patients with advanced cancer. Ann Oncol 5 [Suppl 5]:159
Broggini M, Italia C, Colombo T, Marmonti L, Donelli MG (1984) Activity and distribution of iv and oral 4-demethoxydaunorubicin in murine experimental tumors. Cancer Treat Rep 68:739
Colombo T, Zucchetti M, D'lncalci M (1994) Cyclosporin A markedly changes the distribution of doxorubicin in mice and rats. J Pharmacol Exp Ther 269:22
Croop JM, Raymond M, Haber D, Devault A, Arceci RJ, Gros P, Housman DE (1989) The tree mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues. Mol Cell Biol 9:1346
Duran GE, Gosland MP, Ho AL, Sikic BL (1994) In vitro modulation of multidrug resistance (MDR) using human patient serum from EP-1: a phase I clinical trial of etoposide (VP-16) and SDZ PSC 833. Proc Am Assoc Cancer Res 35:351
Endicott JA, Ling V (1989) The biochemistry of P-glyco-protein-mediated multidurg resistance. Annu Rev Biochem 58: 137
Fisher GA, Hausdorff J, Collins H, Brophy N, Duran GE, Ehsan M, Nix D, Halsey J, Sikic BI (1994) Phase I clinical trial of etoposide with PSC 833, a potent inhibitor of multidrug resistance (MDR). Ann Oncol 5 [Suppl 5]:158
Fojo AT, Ueda K, Slamon DJ, Poplak DG, Gottesman MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumors and tissues Proc Natl Acad Sci USA 84: 265
Ford JM, Hait WN (1990) Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42:155
Friche E, Jensen PB, Nissen NI (1992) Comparison of cyclosporin A and SDZ PSC833 as multidrug-resistance modulators in a daunorubicin-resistant Ehrlich ascites tumor. Cancer Chemother Pharmacol 30:235
Gaveriaux C, Boesch D, Jachez B, Bollinger P, Payne P, Loor F (1991) SDZ-PSC-833, a non-immunosuppressive cyclo-sphorine analog, is a very potent multidrug-resistance modifier. J Cell Pharmacol 2:225
Gottesman MM (1993) How cancer cells evade chemotherapy: 16th Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 53:747
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385
Kaye SB (1993) P-glycoprotein (P-gp) and drug resistance-time for reappraisal? Br J Cancer 67:641
Keller RP, Altermatt HJ, Nooter K, Poschmann G, Laissue JA, Bollinger P, Hiestand PC (1992) SDZ PSC 833, a non-immuno-suppressive cyclosporin: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia. Int J Cancer 50:593
Lum BL, Kaubisch S, Yahanda AM, Adler KM, Jew L, Ehsan MN, Borphy NA, Halsey J, Gosland MP, Sikic BI (1992) Alteration of etoposide pharmacokinetics and pharmacodinamics by cyclosporine in a phase I trial to modulate multidrug resistance. J Clin Oncol 10:1635
Lum BL, Fisher GA, Brophy NA, Yahanda AM, Alder KM, Kaubisch S, Halsey J, Sikic BL (1993) Clinical trials of modulation of multidrug resistance. Cancer 72:3502
Pastan I, Gottesman M (1987) Multidrug resistance in human cancer. N Engl J Med 316:1388
Rushing DA, Raber SR, Rodvold KA, Piscitelli SC, Plank GS, Tewksbury DA (1994) The effects of cyclosporine on the pharmacokinetics of doxorubicin in patients with small cell lung cancer. Cancer 74:834
Sikic BI (1993) Modulation of multidrug resistance: at the threshold. J Clin Oncol 11:1629
Slater LM, Sweet P, Stupecky M, Gupta S (1986) Cyclosporin A reverses vincristine and daunomicin resistance in acute lymphatic leukemia in vitro. J Clin Invest 77:1405
Sonneveld P, Marie JP, Laburte C, Schoester M (1994) Phase I study of SDZ PSC833, a multidrug resistance modulating agent, in refractory multiple myeloma. Proc Am Assoc Cancer Res 35:359
Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S (1988) Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revelaed by a monoclonal antibody, MRK 16. Cancer Res 48:1926
Twentyman PR (1992) Cyclosporins as drug resistance modifiers. Biochem Pharmacol 43:109
Twentyman PR, Bleehen NM (1991) Resistance modification by PSC-833, a novel non-immunosuppressive cyclosporin A. Eur J Cancer 27:1639
Van Der Bliek AM, Borst P (1989) Multidrug resistance. Adv Cancer Res 52:165
Yahanda AM, Alder KM, Fisher GA, Brophy NA, Halsey J, Hardy RI, Gosland MP, Lum BL, Sikic BI (1992) Phase I trial of etoposide with cylosporine as a modulator of multidrug resistnace. J Clin Oncol 10:1624
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gonzalez, O., Colombo, T., De Fusco, M. et al. Changes in doxorubicin distribution and toxicity in mice pretreated with the cyclosporin analogue SDZ PSC 833. Cancer Chemother. Pharmacol. 36, 335–340 (1995). https://doi.org/10.1007/BF00689051
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00689051