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Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice

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Abstract

Objectives

c-Myc is commonly activated in many human tumors and is functionally important in cellular proliferation, differentiation, apoptosis and cell cycle progression. The activity of c-Myc requires noncovalent interaction with its client protein Max. In vitro studies indicate the thioxothiazolidinone, 10058-F4, inhibits c-Myc/Max dimerization. In this study, we report the efficacy, pharmacokinetics and metabolism of this novel protein–protein disruptor in mice.

Methods

SCID mice bearing DU145 or PC-3 human prostate cancer xenografts were treated with either 20 or 30 mg/kg 10058-F4 on a qdx5 schedule for 2 weeks for efficacy studies. For pharmacokinetics and metabolism studies, mice bearing PC-3 or DU145 xenografts were treated with 20 mg/kg of 10058-F4 i.v. Plasma and tissues were collected 5–1440 min after dosing. The concentration of 10058-F4 in plasma and tissues was determined by HPLC, and metabolites were characterized by LC-MS/MS.

Results

Following a single iv dose, peak plasma 10058-F4 concentrations of approximately 300 μM were seen at 5 min and declined to below the detection limit at 360 min. Plasma concentration versus time data were best approximated by a two-compartment, open, linear model. The highest tissue concentrations of 10058-F4 were found in fat, lung, liver, and kidney. Peak tumor concentrations of 10058-F4 were at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 were identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 was approximately 1 h, and the volume of distribution was >200 ml/kg. No significant inhibition of tumor growth was seen after i.v. treatment of mice with either 20 or 30 mg/kg 10058-F4.

Conclusion

The lack of significant antitumor activity of 10058-F4 in tumor-bearing mice may have resulted from its rapid metabolism and low concentration in tumors.

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References

  1. Yin X, Giap C, Lazo JS, Prochownik EV (2003) Low molecular weight inhibitors of Myc/Max interaction and function. Oncogene 22:6151–6159

    Article  PubMed  CAS  Google Scholar 

  2. Blum KA, Lozanski G, Byrd JC (2004) Adult Burkitt leukemia and lymphoma. Blood 104:3009–3020

    Article  PubMed  CAS  Google Scholar 

  3. Shaffer AL, Wright G, Yang L, Powell J, Ngo V, Lamy L, Lam LT, Davis RE, Staudt LM (2006) A library of gene expression signatures to illuminate normal and pathological lymphoid biology. Immunol Rev 210:67–85

    Article  PubMed  CAS  Google Scholar 

  4. Berns EM, Klijn JG, Smid M, van Staveren IL, Look MP, van Putten WL, Foekens JA (1996) TP53 and MYC gene alterations independently predict poor prognosis in breast cancer patients. Genes Chromosomes Cancer 16:170–179

    Article  PubMed  CAS  Google Scholar 

  5. Schlotter CM, Vogt U, Bosse U, Mersch B, Wassmann K (2003) c-Myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer. Breast Cancer Res 5:R30–R36

    Article  PubMed  CAS  Google Scholar 

  6. Arango D, Mariadason JM, Wilson AJ, Yang W, Corner GA, Aranes MJ, Augenlicht LH (2003) C-Myc overexpression sensitizes colon cancer cells to camptothecin-induced apoptosis. Br J Cancer 89:1757–1765

    Article  PubMed  CAS  Google Scholar 

  7. Gomez-Curet I, Perkins RS, Bennett R, Feidler KL, Dunn SP, Kruger LJ (2006) c-Myc inhibition negatively impacts lymphoma growth. J Pediatr Surg 41:207–211

    Article  PubMed  Google Scholar 

  8. Huang MJ, Cheng YC, Liu CR, Lin S, Liu E (2006) A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp Hematol 34:1480–1489

    Article  PubMed  CAS  Google Scholar 

  9. Lin CP, Liu JD, Chow JM, Liu CR, Liu HE (2007) Small-molecule c-Myc inhibitor, 10058-F4, inhibits proliferation, downregulates human telomerase reverse transcriptase and enhances chemosensitivity in human hepatocellular carcinoma cells. Anticancer Drugs 18:161–170

    Article  PubMed  CAS  Google Scholar 

  10. Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP, Krueger LJ (2007) MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitts lymphoma cells. Cancer Res 67:9762–9770

    Article  PubMed  CAS  Google Scholar 

  11. Gil J, Kerai P, Lleonart M, Bernard D, Cigudosa JC, Peters G, Carnero A, Beach D (2005) Immortalization of primary human prostate epithelial cells by c-Myc. Clin Cancer Res 65:2179–2185

    CAS  Google Scholar 

  12. Leonetti C, Biroccio A, D’Angelo C, Semple SC, Scarsella M, Zupi G (2007) Therapeutic Integration of c-Myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer. Prostate 67:1475–1485

    Article  PubMed  CAS  Google Scholar 

  13. Nupponen NN, Kakkola L, Koivisto P, Visakorpi T (1998) Genetic alterations in hormone-refractory recurrent prostate carcinomas. Am J Pathol 153:141–148

    PubMed  CAS  Google Scholar 

  14. McGiffie EM, Catapano CV (2002) Design of a novel triple helix forming oligodeoxyribonucleotide directed to the major promoter of the c-myc gene. Nucleic Acids Res 30:2701–2709

    Article  Google Scholar 

  15. Berg T, Cohen SB, Desharnais J, Sonderegger C, Maslyar DJ, Goldberg J, Boger DL, Vogt PK (2002) Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proc Natl Acad Sci USA 99:3830–3835

    Article  PubMed  CAS  Google Scholar 

  16. D’Argenio DZ, Schumitzky A (eds) (1997) ADAPT II user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. University of Southern California, Los Angeles

  17. Akaike H (1979) A Bayesian extension of the minimal AIC procedures of autoregressive model fitting. Biometrika 66:237–242

    Article  Google Scholar 

  18. Rocci ML, Jusko WJ (1983) LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed 16:203–216

    Article  PubMed  Google Scholar 

  19. Jain M, Arvanitis C, Chu K, Dewey W, Leonahardt E, Trinh M, Sundberg CD, Bishop M, Felsher DW (2002) Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297:102–104

    Article  PubMed  CAS  Google Scholar 

  20. Cutrona G, Carpaneto EM, Ponzanelli A, Uliva M, Millo E, Scarfi S, Roncella S, Benatti U, Boffa LC, Ferrarini M (2003) Inhibition of the translocated c-myc in Burkitt’s lymphoma by a PNA Complementary to the Eμ Enhancer. Cancer Res 63:6144–6148

    PubMed  CAS  Google Scholar 

  21. Wang YH, Liu S, Zhang G, Zhou CQ, Zhu HX, Zhou XB, Quan LP, Bai JF, Xu NZ (2005) Knockdown of c-Myc expression by RNAi inhibits MCF-7 breast tumor cells growth in vitro and in vivo. Breast Cancer Res 7:R220–R228

    Article  PubMed  CAS  Google Scholar 

  22. Shen L, Zhang C, Ambrus JL, Wang JH (2005) Silencing of human c-myc oncogene expression by poly-DNP-RNA. Oligonucleotides 15:23–35

    Article  PubMed  CAS  Google Scholar 

  23. Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002) Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-Myc transcription. Proc Natl Acad Sci USA 99:11593–11598

    Article  PubMed  CAS  Google Scholar 

  24. Wang H, Hammoudeh DI, Follis AV, Reese BE, Lazo JS, Metallo SJ, Prochownik EV (2007) Improved low molecular weight Myc–Max inhibitors. Mol Cancer Ther 6:2399–2408

    Article  PubMed  CAS  Google Scholar 

  25. Xiao D, Qu X, Weber C (2002) GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells. Regulatory Peptides 109:141–148

    Article  PubMed  CAS  Google Scholar 

  26. Cassinelli G, Supino R, Zuco V, Lanzi C, Scovassi AI, Semple SC, Zunino F (2004) Role of c-myc protein in hormone refractory prostate carcinoma: cellular response to paclitaxel. Biochem Pharmacol 68:923–932

    Article  PubMed  CAS  Google Scholar 

  27. Bernard D, Pourtier-Manzanedo A, Gil J, Beach DH (2003) Myc confers androgen-independent prostate cancer cell growth. J Clin Invest 112:1724–1737

    PubMed  CAS  Google Scholar 

  28. Yoshimura I, Wu JM, Chen Y, Ng C, Mallouh C, Backer JM, Mendola CE, Tazaki H (1995) Effects of 5-α-Dihydrotestosterone (DHT) on the transcription of nm23 and c-myc genes in human prostatic LNCaP cells. Biochem Biophy Res Commun 208:603–609

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported in part by NIH CA78039 and DOD W81XWH-04-1-0226. We would like to thank Diane Mazzei and the staff of the DLAR for the excellent care of the animals and the UPCI writing group for their helpful suggestions regarding this manuscript.

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Authors and Affiliations

  1. Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Room G27b. 5117 Centre Ave., Pittsburgh, PA, 15213, USA

    Jianxia Guo, Robert A. Parise, Erin Joseph, Merrill J. Egorin & Julie L. Eiseman

  2. Department of Pharmacology, The University of Pittsburgh Cancer Institute, Room G27b. 5117 Centre Ave., Pittsburgh, PA, 15213, USA

    John S. Lazo

  3. Section of Hematology/Oncology, Children’s Hospital, Pittsburgh, PA, USA

    Edward V. Prochownik

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  1. Jianxia Guo
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  2. Robert A. Parise
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  3. Erin Joseph
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  4. Merrill J. Egorin
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  5. John S. Lazo
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  7. Julie L. Eiseman
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Correspondence to Julie L. Eiseman.

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Guo, J., Parise, R.A., Joseph, E. et al. Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice. Cancer Chemother Pharmacol 63, 615–625 (2009). https://doi.org/10.1007/s00280-008-0774-y

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  • DOI: https://doi.org/10.1007/s00280-008-0774-y

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