Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy (eBook)

Platinum chemotherapy: an oncologic success story Lawerence H. Einhorn Platinum compounds in clinical development Hilary Calvert Satraplatin: overview Cristiana Sessa Satraplatin in prostate cancer Cora Sternberg New formulations Roman Perez-Soler Novel drug delivery systems: AP5346 Stephen B. Howell CTR1 as a determinant of platinum drug transport Stephen B. Howell ATP7B regulates intracellular sequestration of Pt drugs Rouhi Safaei Molecular alterations of oxaliplatin-resistant cell exhibiting accumulation defects Paola Perego How to overcome cisplatin resistance through proton pump inhibitors Stefano Fais Multiple mechanisms of resistance to cisplatin in cancer cells Michael Gottsman Platinum drug damage to DNA and nucleosomes: recognition/repair and cell-response mechanisms Stephen J. Lippard Molecular rationale to improve platinum selectivity Maurizio D’Incalci Recognition and processing of platinum drugs-DNA adducts Stephen G. Chaney Platinum drugs and DNA repair: lessons from the NCI-60 panel and clinical correlates Jacques Robert Effects of platinated compounds in signal transduction: role of interaction with other drugs Godefridus J. Peters Platinum drugs as radio-sensitizer Silvia Formenti Head and Neck cancer Lisa Licitra Non-colorectal cancer Florian Lordick Colorectal cancer Andrea Bonetti New drugs for the management of chemotherapy-induced nausea and vomiting Matti Aapro Breast cancer Luca Gianni Ovarian cancer Franco Muggia Cancer of the uterus Paul Hoskins Lung cancer Giuseppe Giaccone Heavy metal compounds in cancer chemotherapy: positive findings Gianni Sava, Heavy metal compounds in cancer chemotherapy: negative findings Jan Schellens Neurotoxicity Guido Cavalletti Anemia and myelosuppression Fabio Benedetti Platinum drugs and the children with cancer Riccardo Riccardi Allergic reactions Eleni Andreopoulou Optimizing dose using patient characteristics Etienne Chatelut The real impact of intraperitoneal chemotherapy in ovarian cancer Franco Muggia IP Therapy - Where do we go from here Stephen B Howell

Studies on New Platinum Compounds (S. 11-12)

Fazlul Huq, Jun Qing Yu, and Philip Beale

Abstract
This chapter provides a review of the activities of a number of recently synthesized planaramineplatinum(II) complexes and platinum compounds with multiple metal centers against human ovarian cancer cell lines. Planaramineplatinum complexes code named YH12 and CH1 are found to be significantly more active than cisplatin in the resistant ovarian cancer cell lines A2780 cisR and A2780 ZD0473R. The compound code-named CH3 contains three 3-hydroxypyridine ligands bound to platinum(II) and therefore can only form a monofunctional Pt(G) adduct and is found to be significantly active, thus indicating that the formation of bifunctional adducts with DNA may not be an essential requirement for activity. Among compounds containing multiple metal centers, DH6Cl and TH1 are much more active than cisplatin.

Keywords
Planaramineplatinum complexes, Ovarian cancer cell lines

Introduction
Widespread use in clinics and increasing volume of sales indicate that even in the postgenomic age there is a need for the type of shotgun chemotherapy provided by platinum drugs. Although thousands of cisplatin analogues have been prepared by changing the nature of the leaving groups and carrier ligands, resulting in much reduced toxicity, only a limited change in the spectrum of activity has been achieved. Therefore attention is currently being given to rule-breaker platinum compounds, with the aim of widening the spectrum of activity and reducing the side effects associated with platinum-based chemotherapy (1–4).

Two such classes of compounds are trans-planaramineplatinum(II) complexes and compounds containing two or more platinum centers. One of the main reasons for the limited spectrum of activity of platinum drugs is the drug resistance that may be intrinsic and/or acquired. This paper provides a review of the work on new mononuclear and multinuclear platinum complexes carried out in our laboratory. Some of the complexes were found to be significantly more active than cisplatin against ovarian cancer cell lines (5–18).

Planaramineplatinum(II) Complexes

Figure 1 gives the structures of a number of planaramineplatinum(II) complexes of the forms: Pt(L)(NH3)Cl2, PtL2X2 and PtL3X (where L = a planaramine ligand and X = Cl- except in the case of AH8 where X = I-) that have been synthesized, characterized, and investigated for activity against human ovarian cancer cell lines A2780, A2780 cisR and A2780 ZD0473R. The cell uptake and level of binding with nuclear DNA have also been determined. Table 1 gives the IC50 values of YH9, YH10, YH11, YH12, CH1, CH2, CH3 and CH4 against the human ovarian cancer cell lines A2780, A2780 cisR and A2780 ZD0473R.

Although cis-planaramineplatinum(II) complexes (with the exception of the totally inactive compound AH8 that has two iodide leaving groups) are found to be more active than the corresponding trans-planaramineplatinum(II) complexes, their resistance factors are generally larger. For example, AH5 is more active than YH12 against the A2780 cell line but less so against the A2780 cisR cell line. The results indicate that cis-planaramineplatinum(II) complexes have greater crossresistance with cisplatin than the corresponding trans compounds.

The results may also be seen to provide support to the idea that the increased DNA repair is a dominant mechanism of resistance operating in the ovarian cancer cell lines. As cis-planaramineplatinum(II) complexes, like cisplatin, are expected to form mainly bifunctional intrastrand Pt(GG) adducts and trans-planaramineplatinum(II) complexes are more likely to form interstrand Pt(GG) adducts, it follows that the DNA repair in cis-planaramineplatinum(II) complexes may involve the removal of intrastrand Pt(GG) adducts.