Complexes and Conjugates of cis-Pt for Immunotargeted Chemotherapy

  • Ruth Arnon
  • Bilha Schechter
  • Meir Wilchek
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 303)

Abstract

A major problem in cancer chemotherapy is how to enhance the effectiveness of currently available anti cancer drugs. Due to the lack of selectivity of cytotoxic agents, the administration of single drug doses is restricted to sub-toxic levels. Drug clearance and excretion and/or metabolic conversion of the drug result in only transient increased levels at the tumor site which are generally insufficient to effect complete cure. The problem is therefore, how to attain sufficient amounts of drug at the tumor site for the required period of time, without using drug doses which are above the threshold of toxicity. One possible way is to use molecules with inherent or acquired ability to interact selectively with the target organ, e.g. anti-tumor antibodies, as carriers for the drug, thus leading to specific targeting to the tumor site. An alternative approach is to attach anti-cancer agents to polymeric carriers that will act as control release units by affecting the biodistribution and maintenance of the drug. These delivery devices may cause retardation of drug clearance or inactivation as well as prolonged or sustained release of the drug at non-toxic levels, thus overcoming the problem of harmful peak concentrations. Such polymeric drug systems, in addition to being advantageous to the free drug as such, may be also used for conjugation to antitumor antibodies for the purpose of immunotargeting.

Keywords

Toxicity Lymphoma Platinum Carboxyl Oncol 

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References

  1. 1.
    A.W. Prestayko, J.C. D’Aoust, B.F. Issel and S.T. Crooke, Cisplatin (cis-diamminedichloroplatinum II). Cancer Treat. Rev., 6: 17 (1979).PubMedCrossRefGoogle Scholar
  2. 2.
    B.J. Corden, R.L. Fine, R.F. Ozols and J.M. Collins. Chemical pharmacology of high-dose cisplatin. Cancer Chemother. Pharmacol., 14: 38 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    R.F. Ozols and R.C. Young. High-dose cisplatin therapy in ovarian cancer. Semin. Oncol. 21:12 (1985).Google Scholar
  4. 4.
    J.J. Roberts. Mechanism of action of antitumor platinum compounds. In: Molecular mechanisms of carcinogenic and antitumor activity. C. Chagas and B. Pullman, eds. Pontificia Academia Scientiarvm. (1986).Google Scholar
  5. 5.
    M.E. Howe-Grant and S.J. Lippard. Aqueous platinum(II) chemistry: Binding to boilogical molecules. In: “Metal ions in biological systems”. H. Sigel, ed. Marcel Dekker, New York. 11:63 (1980).Google Scholar
  6. 6.
    D.A. Juckett and B. Rosenberg. Actions of cis-diamminedichloroplatinum on cell surface nucleic acids in cancer cells as determined by cell electrophoresis techniques. Cancer Res, 42:3562 (1982).Google Scholar
  7. 7.
    S. Shionoya, Y. Lu and K.J. Scanlon. Properties of amino acid and transport systems in K562 cells sensitive and resistant to cis-diamminedichloroplatinum(II). Cancer Res, 46:3445 (1986).PubMedGoogle Scholar
  8. 8.
    B. Schechter, R. Pauzner, R. Arnon and M. Wilchek. Cis-platinum(II) complexes of carboxymethyl dextran as potential antitumor agents. I. Preparation and characterization. Cancer Biochem. Biophys. 8: 277 (1986).PubMedGoogle Scholar
  9. 9.
    B. Schechter, R. Pauzner, M. Wilchek, and R. Arnon. Cis-platinum(II) complexes of carboxymethyl dextran as potential antitumor agents. II. In-vitro and in-vivo activity. Cancer Biochem Biophys. 8: 289 (1986).PubMedGoogle Scholar
  10. 10.
    B. Schechter, A. Neumann, M. Wilchek and R. Arnon. Soluble polymers as carriers of cis-platinum. J. of Controlled Release. 10: 75 (1989).CrossRefGoogle Scholar
  11. 11.
    J.J. Gullo, C.L. Litterst, P.J. Maguire, B.I. Sikie, D.F. Hoth and P.V. Woolley. Pharmacokinetics and protein binding of cis-dichlorodiammine platinum(II) administration as a one hour, or as a twenty hour infusion. Cancer Chemother. Pharmacol, 5: 21 (1980).PubMedCrossRefGoogle Scholar
  12. 12.
    C.L. Litterst, T.E. Gram, R.L. Dedrick, A.F. Leroy and A.M. Guarino. Distribution and disposition of cis-diamminedichloroplatinum(II). (NCS-1198-75) in dogs. Cancer Res, 36: 2340 (1976).Google Scholar
  13. 13.
    B. Schechter, M.A. Rosing, M. Wilchek, and R. Arnon. Blood levels and serum-protein binding of cis-platinum(II) complexed to carboxymethyl-dextran. Cancer Chememother. Pharmacol, 24: 661 (1989).Google Scholar
  14. 14.
    J. Schlessinger. Allosteric regulation of the epidermal growth factor receptor kinase. J. Cell Biol, 103: 2067 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    E. Aboud-Pirak, E. Hurwitz, M.E. Pirak, F. Bellot, J. Schlessinger, and M. Sela. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in-vitro and in nude mice. J. Natl. Cancer Inst. 80: 1605, (1988).PubMedCrossRefGoogle Scholar
  16. 16.
    M. Wilchek and E.A. Bayer. The avidin and biotin complex in biological applications. Analytical Biochemistry. 171: 1 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    D.J. Hnatowich, F. Virzi and M. Rusckowski. Investigations of avidin and biotin for imaging applications. J. Nuclear Med, 28: 1294 (1987).Google Scholar
  18. 18.
    G. Paganelli. S. Prerez, A.G. Siccardi, G. Rowlinson, G., Deleide, F. Chiolerio, M. Malcovati, G.A. Scassellati, and Epenetos, A.A. Intraperitoneal radio-localization of tumors pre-targeted by biotinylated monoclonal antibodies. Int. J. Cancer, 45: 1184 (1990).PubMedCrossRefGoogle Scholar
  19. 19.
    B. Schechter, R. Silberman, R. Arnon and M. Wilchek. Tissue distribution of avidin and streptavidin injected to mice. Eur. J. Biochem, 189:327 (1990).PubMedCrossRefGoogle Scholar
  20. 20.
    B. Schechter, R. Pauzner, R. Arnon, J. Haimovich, and M. Wilchek. Selective cytotoxicity against tumor cells by cisplatin complexed to antitumor antibodies via carboxymethyl dextran. Cancer Immunol. Immunother, 25: 225 (1987).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Ruth Arnon
    • 1
    • 2
  • Bilha Schechter
    • 1
    • 2
  • Meir Wilchek
    • 1
    • 2
  1. 1.Department of Chemical ImmunologyRehovotIsrael
  2. 2.Department of BiophysicsRehovotIsrael

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