Toxic Effects of Metallopharmaceuticals

Open access


Discovery of the metallopharmaceutical cisplatin and its use in antitumour therapy has initiated the rational design and screening of metal-based anticancer agents as potential chemotherapeutics. In addition to the achievements of cisplatin and its therapeutic analogues, there are significant drawbacks to its use: resistance and toxicity. Over the past four decades, numerous transition metal complexes have been synthesized and investigated in vitro and in vivo. The most studied metals among these complexes are platinum and ruthenium. The key features of these investigations is to find novel metal complexes that could potentially exert less toxicity and equal or higher antitumour potency and to overcome other pharmacological deficiencies. Ru complexes have a different mode of action than cisplatin does, some of which are under clinical trials for treating metastatic or cisplatin-resistant tumours. This review consists of the current knowledge, published and unpublished, related to the toxicity of metallopharmaceuticals, and special attention is given to platinum [Pt(II) and Pt(IV)] and ruthenium [Ru(II) and Ru(III)] complexes.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Jakupec MA Galanski M & Keppler BK. (2003). Tumour- inhibiting platinum complexes--state of the art and future perspectives. Reviews of Physiology Biochemistry and Pharmacology 146 1-54.

  • 2. Sakurai H. (2010). Overview and frontier for the development of metallopharmaceutics. Journal of Health Science 56(2) 129-143.

  • 3. Clarke MJ Zhu F & Frasca DR. (1999). Non-platinum chemotherapeutic metallopharmaceuticals. Chemical Reviews 99(9) 2511-2534.

  • 4. Donzelli E Carfi M Miloso M Strada A Galbiati S Bayssas M Griffon-Etienne G Cavaletti G Petruccioli MG & Tredici G. (2004). Neurotoxicity of platinum compounds: comparison of the effects of cisplatin and oxaliplatin on the human neuroblastoma cell line SHSY5Y. Journal of Neuro-oncology 67(1-2) 65-73.

  • 5. Allardyce CS & Dyson PJ. (2001). Ruthenium in medicine: current clinical uses and future prospects. Platinum Metals Review 45(2) 62-69.

  • 6. van Rijt SH & Sadler PJ (2009). Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs. Drug Discovery Today 14(23) 1089-1097.

  • 7. Kelland L. (2007). The resurgence of platinum-based cancer chemotherapy. Nature Reviews Cancer 7(8) 573-584.

  • 8. Stachurska A Dudkowska M Czopek A Manteuffel- Cymborowska M & Grzelakowska-Sztabert B. (2004). Cisplatin up-regulates the in vivo biosynthesis and degradation of renal polyamines and c-Myc expression. Biochimica et Biophysica Acta 1689(3) 259-266.

  • 9. Cassidy J & Misset JL. (2002). Oxaliplatin-related side effects: characteristics and management. Seminars in Oncology 29(5 Suppl 15) 11-20.

  • 10. Yao X Panichpisal K Kurtzman N & Nugent K. (2007). Cisplatin nephrotoxicity: a review. The American Journal of the Medical Sciences 334(2) 115-124.

  • 11. Goldstein RS & Mayor GH. (1983). The nephrotoxicity of cisplatin. Life Sciences 32(7) 685-690.

  • 12. Kroning R Katz D Lichtenstein AK & Nagami GT. (1999). Differential effects of cisplatin in proximal and distal renal tubule epithelial cell lines. British Journal of Cancer 79(2) 293-299.

  • 13. Fjeldborg P Sorensen J & Helkjaer PE. (1986). The long-term effect of cisplatin on renal function. Cancer 58(10) 2214-2217.

  • 14. Daugaard G Rossing N & Rorth M. (1988). Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemotherapy and Pharmacology 21(2) 163-167.

  • 15. Moul JW Robertson JE George SL Paulson DF & Walther PJ. Complications of therapy for testicular cancer. (1989). The Journal of Urology 142(6) 1491-1496.

  • 16. Keppler BK Henn M Juhl U M Berger MR Niebl R & Wagner FE. (1989). New ruthenium complexes for the treatment of cancer. In Baulieu E Forman DT Ingelman- Sundberg M Jaenicke L Kellen JA Nagai Y Springer GF Trager T Will-Shahab LWittliff JL (Eds.) Ruthenium and Other Non-Platinum Metal Complexes in Cancer Chemotherapy (pp. 41-69). Springer Berlin Heidelberg.

  • 17. Meijer C de Vries EG Marmiroli P Tredici G Frattola L & Cavaletti G. (1999). Cisplatin-induced DNA-platination in experimental dorsal root ganglia neuronopathy. Neurotoxicology 20(6) 883-887.

  • 18. Thompson SW Davis LE Kornfeld M Hilgers RD & Standefer JC. (1984). Cisplatin neuropathy. Clinical electrophysiologic morphologic and toxicologic studies. Cancer 54(7) 1269-1275.

  • 19. Markman M Kennedy A Webster K Kulp B Peterson G & Belinson J. (2001). Neurotoxicity associated with a regimen of carboplatin (AUC 5-6) and paclitaxel (175 mg/m2 over 3 h) employed in the treatment of gynecologic malignancies. Journal of Cancer Research and Clinical Oncology 127(1) 55-58.

  • 20. Gamelin E Gamelin L Bossi L & Quasthoff S. (2002). Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Seminars in Oncology 29(5) 21-33.

  • 21. Gamelin L Boisdron-Celle M Delva R Guerin-Meyer V Ifrah N Morel A & Gamelin E. (2004). Prevention of Oxaliplatin-Related Neurotoxicity by Calcium and Magnesium Infusions A Retrospective Study of 161 Patients Receiving Oxaliplatin Combined with 5-Fluorouracil and Leucovorin for Advanced Colorectal Cancer. Clinical Cancer Research 10(12) 4055-4061.

  • 22. Ding D Allman BL & Salvi R. (2012). Review: ototoxic characteristics of platinum antitumor drugs. Anatomical Record (Hoboken N.J.: 2007). 295(11) 1851-1867.

  • 23. Ravi R Somani SM & Rybak LP. (1995). Mechanism of cisplatin ototoxicity: antioxidant system. Pharmacology & Toxicology 76(6) 386-394.

  • 24. Bokemeyer C Berger CC Hartmann JT Kollmannsberger C Schmoll HJ Kuczyk MA & Kanz L. (1998). Analysis of risk factors for cisplatin-induced ototoxicity in patients with testicular cancer. British Journal of Cancer 77(8) 1355-1362.

  • 25. Reddel RR Kefford RF Grant J M Coates AS Fox RM & Tattersall M H. (1982). Ototoxicity in patients receiving cisplatin: importance of dose and method of drug administration. Cancer Treatment Reports 66(1) 19-23.

  • 26. Skinner R Pearson AD Amineddine HA Mathias DB & Craft AW. (1990). Ototoxicity of cisplatinum in children and adolescents. British Journal of Cancer 61(6) 927-933.

  • 27. Deavall DG Martin EA Horner JM & Roberts R. (2012). Drug-induced oxidative stress and toxicity. Journal of Toxicology 2012 645460.

  • 28. van der Hulst RJ Dreschler WA & Urbanus NA. (1988). High frequency audiometry in prospective clinical research of ototoxicity due to platinum derivatives. Annals of Otology Rhinology & Laryngology 97(2 Pt 1) 133-137.

  • 29. Hansen SW & Olsen N. (1989). Raynaud’s phenomenon in patients treated with cisplatin vinblastine and bleomycin for germ cell cancer: Measurement of vasoconstrictor response to cold. Journal of Clinical Oncology 7(7) 940-942.

  • 30. Vogelzang NJ Bosl GJ Johnson K & Kennedy BJ. (1981). Raynaud’s phenomenon: A common toxicity after combination chemotherapy for testicular cancer. Annals of Internal Medicine 95(3) 288-292.

  • 31. Masuda H Tanaka T & Takahama U. (1994). Cisplatin generates superoxide anion by interaction with DNA in a cell-free system. Biochemical and Biophysical Research Communications 203(2) 1175-1180.

  • 32. Santos NAG Catao CS Martins NM Curti C Bianchi MLP & Santos AC. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress redox state unbalance impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology 81(7) 495-504.

  • 33. Stojic I Zivkovic V Srejovic I Jeremic N Jakovljevic V Djuric D & Novokmet S. (2016). The Effects of Cisplatin and Its Pt(II) Analogue on Oxidative Stress of Isolated Rat Heart. Serbian Journal of Experimental and Clinical Research 17(1) 15-20.

  • 34. Misic MM Jakovljevic VL Bugarcic ZD Zivkovic VI Srejovic IM Barudzic NS Djuric DM & Novokmet SS. (2015). Platinum Complexes-Induced Cardiotoxicity of Isolated Perfused Rat Heart: Comparison of Pt(II) and Pt(IV) Analogues Versus Cisplatin. Cardiovascular Toxicology 15(3) 261-268.

  • 35. Dougan SJ Habtemariam A McHale SE Parsons S & Sadler PJ. (2008). Catalytic organometallic anticancer complexes. Proceedings of the National Academy of Sciences 105(33) 11628-11633.

  • 36. Levina A Mitra A & Lay PA. (2009). Recent developments in ruthenium anticancer drugs. Metallomics 1(6) 458-470.

Journal information
Impact Factor

CiteScore 2018: 0.13

SCImago Journal Rank (SJR) 2018: 0.118
Source Normalized Impact per Paper (SNIP) 2018: 0.079

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 234 141 9
PDF Downloads 141 86 6