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Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein

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Abstract

Purpose

Camptothecins contain a lactone ring that is necessary for antitumor activity, and hydrolysis of the lactone ring yields an inactive carboxylate species. Human serum albumin (HSA) and alpha-1 acid glycoprotein (AGP) are clinically significant plasma proteins thought to have important roles in camptothecin lactone stability. Herein, we examined the effect(s) of HSA and AGP on the lactone stability of Karenitecin, a novel, highly lipophilic camptothecin analog, currently at the phase 3 clinical testing stage.

Methods

An AGP-immobilized protein column was used to develop HPLC methods to evaluate the effect(s) of physiologically relevant HSA and AGP concentrations on the lactone/carboxylate ratio and hydrolysis kinetics of Karenitecin, camptothecin (CPT), and topotecan (TPT).

Results

Physiologically relevant concentrations of HSA and AGP substantially slowed Karenitecin lactone hydrolysis. AGP was notably more effective at protecting the Karenitecin lactone from hydrolysis than HSA was in promoting hydrolysis. Additionally, AGP reversed the hydrolysis of partially hydrolyzed Karenitecin lactone. In contrast, HSA and AGP had minimal effects on hydrolysis of the TPT lactone, while the AGP/HSA solutions dramatically accelerated hydrolysis of the CPT lactone.

Conclusion

AGP strongly enhances the lactone stability of Karenitecin. Since Karenitecin is highly protein-bound in human plasma and exhibits greater lactone stability, relative to other camptothecins, in patient plasma samples, this newly identified role of AGP in promoting lactone stability may have important implications for the design of more effective anticancer agents within the Karentecin™ and camptothecin classes.

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References

  1. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail HT, Sim GA (1966) Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata. J Am Chem Soc 88:3888–3890

    Article  CAS  Google Scholar 

  2. Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS (1972) Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 56:515–521

    CAS  PubMed  Google Scholar 

  3. Sparreboom A and Zamboni WC (2007) Topoisomerase I-targeting drugs. In: Cancer chemotherapy and biotherapy: principles and practice, 4:371–413

  4. Daud A, Valkov N, Centeno B, Derderian J, Sullivan P, Munster P, Urbas P, Deconti RC, Berghorn E, Liu Z, Hausheer F, Sullivan D (2005) Phase II trial of karenitecin in patients with malignant melanoma: clinical and translational study. Clin Cancer Res 11:3009–3016

    Article  CAS  PubMed  Google Scholar 

  5. Grossman SA, Carson KA, Phuphanich S, Batchelor T, Peereboom D, Nabors LB, Lesser G, Hausheer F, Supko JG (2008) Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas. Neuro Oncol 10:608–616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Smith JA, Hausheer F, Newman RA, Madden TL (2001) Development of a high-performance liquid chromatographic method to determine the concentration of karenitecin, a novel highly lipophilic camptothecin derivative, in human plasma and urine. J Chromatogr B Biomed Sci Appl 759:117–124

    Article  CAS  PubMed  Google Scholar 

  7. Smith JA, Newman RA, Hausheer FH, Madden T (2003) Evaluation of in vitro drug interactions with Karenitecin, a novel, highly lipophilic camptothecin derivative in phase II clinical development. J Clin Pharmacol 43:1008–1014

    Article  CAS  PubMed  Google Scholar 

  8. Van Hattum AH, Pinedo HM, Schluper HM, Hausheer FH, Boven E (2000) New highly lipophilic camptothecin BNP1350 is an effective drug in experimental human cancer. Int J Cancer Res 88(2):260–266

    Article  Google Scholar 

  9. Van Hattum AH, Schluper HM, Hausheer FH, Pinedo HM, Boven E (2002) Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of efficacy and possible mechanisms of resistance. Int J Cancer 100:22–29

    Article  PubMed  Google Scholar 

  10. Keir ST, Hausheer F, Lawless AA, Bigner DD, Friedman HS (2001) Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice. Cancer Chemother Pharmacol 48:83–87

    Article  CAS  PubMed  Google Scholar 

  11. Hausheer FH, Haridas K, Zhao M, Murali D, Seetharamalu P, Yao S, Reddy D, Pavankumar P, Wu M, Saxe J, Huang Q, Rustum Y (1998) Abstract #2862: Karenitecins (Part II): a novel class of orally active highly lipophilic topoisomerase I inhibitors. Proceedings of the AACR 39:420–421

    Google Scholar 

  12. Maliepaard M, van Gastelen MA, Tohgo A, Hausheer FH, van Waardenburg RC, de Jong LA, Pluim D, Beijnen JH, Schellens JH (2001) Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in Vitro using non-substrate drugs or the BCRP inhibitor GF120918. Clin Cancer Res 7:935–941

    CAS  PubMed  Google Scholar 

  13. Camptosar Package Insert. http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20571s16lbl.pdf

  14. Hycamtin Package Insert. https://www.gsksource.com/gskprm/htdocs/documents/HYCAMTIN-FOR-INJ.PDF

  15. Thompson PA, Berg SL, Aleksic A, Kerr JZ, McGuffey L, Dauser R, Nuchtern JG, Hausheer F, Blaney SM (2004) Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates. Cancer Chemother Pharmacol 53:527–532

    Article  CAS  PubMed  Google Scholar 

  16. Otagiri M (2005) A molecular functional study on the interactions of drugs with plasma proteins. Drug Metab Pharmacokinet 20:309–323

    Article  CAS  PubMed  Google Scholar 

  17. Burke TG, Mi Z (1993) Preferential binding of the carboxylate form of camptothecin by human serum albumin. Anal Biochem 1:285–287

    Article  Google Scholar 

  18. Burke TG, Mi Z (1993) Ethyl substitution of the 7 position extends the half-life of 10-hydroxycamptothecin in the presence of human serum albumin. J Med Chem 36(17):2580–2582

    Article  CAS  PubMed  Google Scholar 

  19. Burke TG, Mi Z (1994) The structural basis of camptothecin interactions with human serum albumin: impact on drug stability. J Med Chem 37:40–46

    Article  CAS  PubMed  Google Scholar 

  20. Burke TG (1996) Chemistry of the camptothecins in the bloodstream. Drug stabilization and optimization of activity. Ann N.Y Acad Sci 803:29–31

    Article  CAS  PubMed  Google Scholar 

  21. Mi Z, Burke TG (1994) Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 33:10325–10336

    Article  CAS  PubMed  Google Scholar 

  22. Mi Z, Malak H, Burke TG (1995) Reduced albumin binding promotes the stability and activity of topotecan in human blood. Biochemistry 34:13722–13728

    Article  CAS  PubMed  Google Scholar 

  23. Bertucci C, Domenici E (2002) Reversible and covalent binding of drugs to human serum albumin: methodological approaches and physiological relevance. Curr Med Chem 9:1463–1481

    Article  CAS  PubMed  Google Scholar 

  24. Peters T Jr (1996) Metabolism: albumin in the body, 4th edn., All about albumin: biochemistry, genetics, and medical applicationsAcademic Press Inc, San Diego, pp 188–250

    Google Scholar 

  25. Hage DS, Jackson A, Sobansky MR, Schiel JE, Yoo MJ, Joseph KS (2009) Characterization of drug-protein interactions in blood using high-performance affinity chromatography. J Sep Sci 32:835–853

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Cheresh DA, Haynes DH, Distasio JA (1984) Interaction of an acute phase reactant, alpha 1-acid glycoprotein (orosomucoid), with the lymphoid cell surface: a model for non-specific immune suppression. Immunology 51:541–548

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Mi Z, Burke TG (1994) Marked interspecies variations concerning the interactions of camptothecin with serum albumins: a frequency-domain fluorescence spectroscopic study. Biochemistry 33:12540–12545

    Article  CAS  PubMed  Google Scholar 

  28. Bom D, Curran DP, Kruszewski S, Zimmer SG, Thompson SJ, Kohlhagen G, Du W, Chavan AJ, Fraley KA, Bingcang AL, Latus LJ, Pommier Y, Burke TG (2000) The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 43:3970–3980

    Article  CAS  PubMed  Google Scholar 

  29. Evans TW (2002) Albumin as a drug—biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther 16(Suppl 5):6–11

    Article  CAS  PubMed  Google Scholar 

  30. Israili ZH, Dayton PG (2001) Human alpha-1-glycoprotein and its interactions with drugs. Drug Metab Rev 33:161–235

    Article  CAS  PubMed  Google Scholar 

  31. Kurono Y, Miyajima M, Ikeda K (1993) Interaction of camptothecin derivatives with human plasma proteins in vitro. Yakugaku Zasshi 113:167–175

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. BioNumerik Pharmaceuticals, Inc., 8122 Datapoint Drive, Suite 1250, San Antonio, TX, 78229, USA

    Shijie Yao, Pavankumar Petluru, Aulma Parker, Daoyuan Ding, Xinghai Chen, Qiuli Huang, Harry Kochat & Frederick Hausheer

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  1. Shijie Yao
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  2. Pavankumar Petluru
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  3. Aulma Parker
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  4. Daoyuan Ding
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  5. Xinghai Chen
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  7. Harry Kochat
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  8. Frederick Hausheer
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Correspondence to Pavankumar Petluru.

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Yao, S., Petluru, P., Parker, A. et al. Stabilization of the Karenitecin® lactone by alpha-1 acid glycoprotein. Cancer Chemother Pharmacol 75, 719–728 (2015). https://doi.org/10.1007/s00280-015-2686-y

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  • DOI: https://doi.org/10.1007/s00280-015-2686-y

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