Abstract
Cancerous diseases, together with cardiac afflictions, account for the predominant causes of death among the adult population of the Western world. The classical platinum drugs, with cisplatin as their parent, have established themselves for years as leading components in the oncologist’s arsenal of antitumor agents. As with most other antineoplastic drugs, however, incisive pharmacological deficiencies, notably excessive systemic toxicity and induction of drug resistance, have severely curtailed their overall efficaciousness. With the objective of overcoming these counterproductive deficiencies, the technique of polymer-drug conjugation, representing an advanced modality of drug delivery, has been developed in recent years to high standards worldwide. In a drug conjugate, water-soluble macromolecular carrier constructs designed in compliance with stringent pharmacological specifications are covalently, yet bioreversibly, interconnected with the bioactive agent. As a macromolecule following a pharmacokinetic pathway different from that of non-polymeric compounds, the conjugate acts as a pro-drug favorably transporting the agent through the various body compartments to, and into, the target cell, where the agent is enzymatically or hydrolytically separated from the carrier for its biological action. In the authors’ laboratories the conjugation strategy has been adopted as the primary tool for drug efficacy enhancement. The present paper describes a special type of platinum complex carrier-bound via dicarboxymetal chelation, synthesized from carboxyl-functionalized polyamide-type carriers by platination with trans-1,2-diaminocyclohexanediaquaplatinum(II) dinitrate. In a series of in vitro tests antiproliferative activities have been determined against several human cancer cell lines. Whereas no improvements are observed in tests against a colorectal cancer, outstanding findings of the screening program include a 10- to 100-fold increase in cell-killing performance of the conjugates relative to the (non-polymeric) cisplatin standard against the HeLa adenocarcinoma, and distinctly reduced resistance factors (again, relative to cisplatin) in tests against the A2780 and A2780-cis pair of ovarian cell lines. These findings augur well for future developments of this class of platinum drugs.
Similar content being viewed by others
References
B. Rosenberg, L. van Camp, T. Krigas, Nature 205, 698 (1965). See also: Cancer Chemother. Rep. Part I. 59, 589 (1975)
K.R. Harrap, in Cancer Chemotherapy, vol. 1, Chap. 7, ed. by F.M. Muggia (Martinus Nijhoff, MA, 1983)
J.C. Dabrowiak, W.T. Bradner, Progr. Med. Chem. vol 24, ed. by G.P. Ellis, G.B. West (Elsevier Science Publ., 1987)
W.R. Waud, in Cancer Chemotherapeutic Agents, ed. by W.O. Foye (Am. Chem. Soc, Washington DC, 1995), p. 121
M.J. Cleare, Coord. Chem. Rev. 12, 349 (1974). See also: Dev. Pharmacol. 3, 59 (1983)
M.J. Cleare, J.D. Hoeschele, Platinum Metal. Rev. 6, 17 (1979). See also: Bioionorg. Chem. 2, 187 (1973)
Cisplatin: Current Status and New Developments, ed. by A. Prestayko, S. Crooke, S. Carter (Academic Press, 1980)
N. Farrell, in Transition Metal Complexes as Drugs and Chemotherapeutic Agents (Kluwer Academic, Dordrecht, 1989), p. 67. See also: in Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy, ed. by S.B. Howell (Plenum Press, 1991), p. 81
P.C. Hydes, M.J.H. Russell, Cancer Metastasis Rev. 7, 67 (1988)
S.J. Lippard, Pure Appl. Chem. 59, 731 (1987)
J. Reedijk, A.M.J. Fichtinger-Schepman, A.T. van Oosterom, P. van de Putte, Struct. Bonding 67, 53 (1987). See also: Pure Appl. Chem. 59, 181 (1987); Chem. Rev. 99, 2499 (1999); Chem. Commun. 801 (1996)
E.W. Neuse, C.W.N. Mbonyana, in Inorganic and Metal-containing Polymeric Materials, ed. by J.E. Sheats et al. (Plenum Press, New York, 1990), p. 139
M.J. McKeage, L.R. Kelland, in Molecular Aspects of Drug-DNA Interactions, ed. by S. Neidle, M.J. Waring (MacMillan, New York, 1992), p. 1
L.R. Kelland, Drugs Future 18, 551 (1993). See also: Crit. Revs. Oncol./Hematol. 15, 191 (1993)
C.M. Giandomenico et al., in Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy, ed. by S.B. Howell (Plenum Press, New York, 1991), p. 93
T.W. Hambley, Coord. Chem. Rev. 166, 181 (1997)
E.W. Neuse, Polym. Adv. Technol. 9, 786 (1998)
I. Kostova, Rec. Patents on Anti-Cancer Drug Discov. 1, 1 (2006)
D.W. Siegmann-Louda, C.E. Carraher, in Macromolecules Containing Metal and Metal-like Elements, Vol. 3, Biomedical Applications, Chap. 7, ed. by A.S. Abd-El-Aziz, C.E. Carraher, C.U. Pittman, J.E. Sheats, M. Zeldin (Wiley, 2004)
E.W. Neuse, S. Afr. J. Sci. 95, 509 (1999)
H. Ringsdorf, J. Polym. Sci. Polym. Symp. 51, 135 (1975)
H. Maeda, Adv. Drug Deliv. Rev. 6, 181 (1991), and earlier reports from this author
R. Duncan, J. Kopeček, Adv. Polym. Sci. 57, 51 (1984); ibid 122, 55 (1995)
H.J.-P. Ryser, W.C. Shen, in Targeting of Drugs with Synthetic Systems, ed. by G. Gregoriadis et al. (Plenum Press, 1986), p. 103
C.J.T. Feijen, in Drug Carrier Systems, ed. by F.H.D. Roerdink, A.M. Kroon (Wiley, 1989), p. 57
S.E. Matthews, C.W. Pouton, M.D. Threadgill, Adv. Drug Deliv. Rev. 18, 219 (1996)
H. Maeda, J. Wu, T. Sawa, Y. Matsumura, K. Hori, J. Control Release. 65, 271 (2000)
T. Minko, P. Kopečková, J. Kopeček, Macromol. Symp. 172, 35 (2001)
R. Duncan, Nat. Rev./Drug Discov. 2, 247 (2003)
R.J. Christie, D.W. Grainger, Adv. Drug Deliv. Rev. 55, 421 (2003)
R. Duncan, M.J. Vicent, F. Greco, R.I. Nicholson, Endocr. Relat. Cancer 12, S189 (2005)
A. Nori, J. Kopeček, Adv. Drug Deliv. Rev. 57, 609 (2005)
O. Hovorka, T. Etrych, V. Šubr, J. Strohalm, K. Ulbrich, B. Rihová, J. Drug Target. 14, 391 (2006)
E.W. Neuse, G. Caldwell, J. Inorg. Organometal. Polym. 7, 163 (1997)
E.W. Neuse, B.B. Patel, C.W.N. Mbonyana, J. Inorg. Organometal. Polym. 1, 147 (1991)
G. Caldwell, E.W. Neuse, C.E.J. van Rensburg, J. Inorg. Organometal Polym. 7, 217 (1997)
C.L. Luthy et al., Proc. Int. Symp. Control Rel. Bioact. Mater. 25, 132 (1998)
E. Gianasi, M. Wasil, E.G. Evagorou, A. Keddle, G. Wilson, R. Duncan, Eur. J. Cancer 35, 994 (1999)
C.W.N. Mbonyana, E.W. Neuse, A.G. Perlwitz, Appl. Organometal. Chem. 7, 279 (1993)
E.W. Neuse, A.G. Perlwitz, G. Caldwell, J. Inorg. Organometal. Polym. 5, 195 (1995)
G. Caldwell, E.W. Neuse, A.G. Perlwitz, J. Inorg. Organometal. Polym. 7, 111 (1997)
G. Caldwell, E.W. Neuse, C.E.J. van Rensburg, Appl. Organomet. Chem. 13, 189 (1999)
M.T. Johnson, E.W. Neuse, C.E.J. van Rensburg, E. Kreft, J. Inorg. Organometal. Polym. 13, 55 (2003)
E.W. Neuse, Macromol. Symp. 80, 111 (1994)
E.W. Neuse, Chem. Perspect. 1, 69 (2000)
B. Schechter, A. Neumann, M. Wilchek, R. Arnon, J. Control Release 10, 75 (1989)
D. Avichezer, B. Schechter, R. Arnon, React. Funct. Polym. 36, 59 (1998)
B. Schechter, R. Arnon, Y.E. Freedman, L. Chen, M. Wilchek, J. Drug Target. 4, 171 (1996). See also: React. Polym. 25, 167 (1995)
Y. Ohya, T. Masunaga, T. Baba, T. Ouchi, Pure Appl. Chem. A33, 1005 (1996). See also: J. Biomater. Sci. Polymer Edn. 7, 1085 (1996)
M. Nakashima et al., Biol. Pharm. Bull. 22, 756 (1999)
Y. Ohya, S. Shirakawa, M. Matsumoto, T. Ouchi, Polym. Adv. Technol. 11, 635 (2000)
Y. Ohya, K. Nagatomi, T. Ouchi, Macromol. Biosci. 1, 355 (2001)
Y. Ohya, H. Oue, K. Nagatomi, T. Ouchi, Biomacromolecules 2, 927 (2001)
P. Neri, G. Antoni, F. Benvenuti, F. Cocola, G. Gazzai, J. Med. Chem. 16, 893 (1973)
P. Neri, G. Antoni, Macromol. Synt. 8, 25 (1982)
J. Kalal, J. Drobnĭk, J. Kopeček, J. Exner, Brit. Polym. J. 10, 111 (1978)
J. Drobnĭk, V. Saudek, J. Vlasák, J Kálal, J. Polym. Sci. Polym. Symp. 66, 59, 65 (1979)
J. Pytela, V. Saudek, J. Drobnĭk, F. Rypáček, J. Control Release 10, 17 (1989). See also: Ann. NY Acad. Sci. 446, 258 (1985)
F. Danusso, P. Ferruti, Polymer 11, 88 (1970)
P. Ferruti, M.A. Marchisio, R. Duncan, Macromol. Rapid Commun. 23, 332 (2002), and numerous preceding papers from that group
G. Caldwell, E.W. Neuse, S. Afr. J. Chem. 45, 93 (1992)
G. Caldwell, E.W. Neuse, A. Stephanou, J. Appl. Polym. Sci. 50, 393 (1993)
M.L. de Machado, E.W. Neuse, A.G. Perlwitz, S. Schmitt, Polym. Adv. Technol. 1, 275 (1990)
M.T. Johnson, L.L. Komane, D.D. N’Da, E.W. Neuse, J. Appl. Polym. Sci. 96, 10 (2005)
C.E.J. van Rensburg, A.M. van Staaden, R. Anderson, Cancer Res. 53, 318 (1993)
J.D. Hoeschele, N. Farrell, W.R. Turner, C.D. Rithner, Inorg. Chem. 27, 4106 (1988)
B. Schechter, G. Caldwell, M.G. Meirim, E.W. Neuse, Appl. Organometal. Chem. 14, 701 (2000)
Acknowledgements
The generous support of this project by the Cancer Association of South Africa in conjunction with the THRIP Project, the Medical Research Council, and the Western Platinum Refinery is gratefully acknowledged, and so is the generous donation of solvents by SASOL Ltd. and of a platinum salt by Johnson Matthey Pty. Ltd. Elie Mukaya expresses his gratitude to the Mellon Foundation for a scholarship.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is dedicated to Professor Astruc.
Rights and permissions
About this article
Cite this article
Komane, L.L., Mukaya, E.H., Neuse, E.W. et al. Macromolecular Antiproliferative Agents Featuring Dicarboxylato-Chelated Platinum. J Inorg Organomet Polym 18, 111–123 (2008). https://doi.org/10.1007/s10904-007-9175-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10904-007-9175-7