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Anticancer Platinum Complexes - State of the Art and Future Prospects
Guest Editor: Markus Galanski

Editorial Pp. 1-2

Biochemical Mechanisms of Cisplatin Cytotoxicity Pp. 3-18
V. Cepeda, M.A. Fuertes, J. Castilla, C. Alonso, C. Quevedo and J.M. Pérez
[Abstract] [Full text article]

The Role of Sulfur in Platinum Anticancer Chemotherapy Pp. 19-34
X. Wang and Z. Guo
[Abstract] [Full text article]

NMR Spectroscopy of Anticancer Platinum Drugs Pp. 35-54
J. Vinje and E. Sletten
[Abstract] [Full text article]

Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue Pp 55-73
M. Galanski and B.K. Keppler
[Abstract] [Full text article]

Photoactivatable Platinum Complexes Pp. 75-93
P.J. Bednarski, F.S. Mackay and P.J. Sadler
[Abstract] [Full text article]

Preclinical and Clinical Studies on the Use of Platinum Complexes for Breast Cancer Treatment Pp. 95-110
I. Ott and R. Gust
[Abstract] [Full text article]

Trans-Platinum Complexes in Cancer Therapy Pp. 111-123
M. Coluccia and G. Natile
[Abstract] [Full text article]

Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores Pp. 125-138
R. Guddneppanavar and U. Bierbach
[Abstract] [Full text article]

Abstracts

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Editorial

Cisplatin, carboplatin and oxaliplatin are highly effective metal-based anticancer agents used in 50 % of all tumor therapies all over the world. Besides the fact that these compounds are the sole tumor-inhibiting metal complexes in clinical use, they display a remarkable therapeutic efficacy in a series of solid tumors. In the case of cisplatin, outstanding activity is found in testicular germ cell cancer. Cure rates beyond 90 % are reported; hence, cisplatin is one of the few anticancer agents, exhibiting real curative potential. Additionally, ovarian cancer, non-small cell lung cancer and head and neck cancer are mainly accessible to cisplatin treatment. The second generation platinum drug, carboplatin, shows similar antitumor properties, but considerably reduced side-effects, due to a variation in the ligand sphere around the platinum center. Oxaliplatin was the third platinum complex introduced into the clinics, showing also activity in cis- and carboplatin resistant tumors during the preclinical development. Oxaliplatin now has emerged to the standard treatment option in the case of metastatic colorectal cancer in combination with 5-fluorouracil and leucovorin. Very recently, oxaliplatin was also approved for adjuvant therapy of stage III (Dukes’s C) primary colon cancer, emphasizing the great potential of platinum-based complexes.

Nevertheless, platinum therapy is accompanied by a set of severe dose-limiting adverse effects, such as nephrotoxicity (cisplatin), myelosuppression (carboplatin) and sensory neuropathy (oxaliplatin). Moreover, among others, tinnitus, hearing loss in the high frequency range, impaired vision and gastrointestinal side-effects are known. Additionally, acquired or intrinsic resistance is a serious problem during platinum therapy, resulting in immense efforts in order to design novel and innovative platinum anticancer drugs. Up to date, nearly 40 platinum complexes have been investigated in clinical trials out of thousands in preclinical evaluation. Obviously, it will be difficult to find promising drug candidates within the group of classical anticancer platinum coordination compounds.

Therefore, the aim of this theme issue Anticancer Platinum Complexes - State of the Art and Future Prospects is to cover very recent developments in the field of platinum-based anticancer agents. In the first part, timely in-depth reviews are given about the mechanism of action of platinum complexes, including their processing in the organism, consequently building the basis for a rational drug design, which is reviewed in extenso in the second part of this hot topic issue.

In the first review Biochemical Mechanisms of Cisplatin Cytotoxicity by Cepeda, Fuertes, Castilla, Alonso, Quevedo and Pérez the authors report on the current knowledge about the mechanism of action of cisplatin, including its cellular uptake, DNA damage signals transduction and cell death through apoptosis and necrosis. Cellular DNA in cancer cells is the final target of platinum-based chemotherapy, playing a crucial role in the initiation of apoptotic pathways. However, it is also highlighted that necrosis within the same tumor cell population is observed in parallel to apoptosis. Therefore, an interconnection between these two pathways is hypothesized. The Role of Sulfur in Platinum Anticancer Chemotherapy is of great importance due to the high affinity of sulfur-containing biomolecules like amino acids or proteins to the platinum(II) center. Consequently, Wang and Guo review platinum-sulfur interactions having a high impact on cellular uptake, excretion, resistance, systemic toxicity and cytotoxicity of the administered platinum drugs. Therefore, nearly every process during platinum therapy is dependent on such interactions and it is astonishing that platinum reaches the DNA at all in the presence of sulfur. Additionally, exogenous sulfur-congeners like amifostine and dimesna are also included because of their potential to reduce side-effects and act as cytoprotective agents (rescue agents). The first part of this theme issue, dealing with contributions about the mechanism of action of platinum complexes is completed by Vinje and Sletten. Their review NMR Spectroscopy of Anticancer Platinum Drugs is dedicated to a spectroscopic technique, which is widely used to study the interactions between platinum complexes and biomolecules such as nucleic acid constituents. In this context, both structural and dynamic features are accessible to NMR spectroscopy. Besides the large success in the field of bioinorganic chemistry, based on the dramatic development of modern NMR spectroscopy during the last decade, it is also pointed out that the wide area of protein-platinum interactions is not yet extensively explored.

Novel anticancer platinum complexes should advantageously meet two criteria: they should display a high selectivity for the tumoral tissue and should cause marginal or better no toxic side-effects. This is in principle an unreachable goal in the fight against a complex disease like cancer. In their review Searching for the Magic Bullet: Anticancer Platinum Drugs which can be Accumulated or Activated in the Tumor Tissue Galanski and Keppler describe general strategies in the design of novel and innovative platinum-based anticancer agents. In order to reduce adverse effects, extensive efforts are reported to accumulate platinum complexes by passive or active targeting at the tumor site. These include macromolecular constructs such as tailor-made polymers, micelles and liposomal formulations, but also low molecular-weight complexes, having a high affinity for specific receptors, especially over-expressed in tumor cells. A further strategy trusts in the use of selective activation of the respective complexes in the tumor tissue. In particular, the reducing environment as well as the low pH value found in solid tumors is useful for this purpose. Activation by reduction is also the central point in the case of Photoactivatable Platinum Complexes, which are reviewed by Bednarski, Mackay and Sadler. In contrast, reduction is thereby triggered from outside the organism in tumors, which are accessible to laser-based fiber-optic devices. In this context, two classes of complexes are mainly discussed: diiodo- and diazidoplatinum(IV) compounds. Especially, the diazidoplatinum(IV) agents have shown advantageous pharmacological properties; their reactivity and cytotoxicity is very low in the dark but can be as toxic to cancer cells in the light as cisplatin. Nevertheless, the design of other complexes, which can be sensitized at longer wavelengths, hence increasing the depth light penetrates the tumors, is described to be one major concern of future drug development. The review Preclinical and Clinical Studies on the Use of Platinum Complexes for Breast Cancer Treatment given by Ott and Gust deals with the design of hormonally active and tissue selective platinum complexes, opening up the possibility to treat breast cancer, which is the most frequent epithelial malignancy among women. The authors report on the latest results of preclinical studies as well as on platinum-based combination regimes in clinical trials. In this context, one of the most widely used targets is the estrogen receptor, which is over-expressed in about 60-70 % of cases. On the one hand it is an ideal target for a carrier mediated drug accumulation in hormone dependent tissue, on the other hand it can be used to attack the cells with anti-hormonally agents. Both strategies have been transferred to platinum-based drug design and are discussed in detail. Novel platinum complexes with trans-geometry are reviewed by Coluccia and Natile in their contribution on Trans-Platinum Complexes in Cancer Therapy. In principle this class of complexes exceptionally violates established structure-activity relationships, since transplatin, the trans-isomer of cisplatin, is inactive. Nevertheless, transplatin analogues displaying aromatic N-donor heterocycles, branched aliphatic amines or imino ligands have demonstrated remarkably high cytotoxic potency in comparison to cisplatin, especially in cisplatin refractory or resistant cancer cell lines. First trans-platinum candidates have already been evaluated in vivo, showing promising anticancer properties. The authors highlight that especially the DNA adducts, deriving from trans-platinum interactions, have to be investigated in detail in order to gain a better knowledge, how these lesions are recognized and processed in tumor cells. The second part of this theme issue, focusing on the design of novel anticancer platinum complexes, is completed by Guddneppanavar and Bierbach. In their review Adenine-N3 in the DNA Minor Groove - an Emerging Target for Platinum Containing Anticancer Pharmacophores the authors report on a new class of platinum-acridine conjugates displaying unprecedented platinum-DNA interactions. In contrast to cisplatin and analogues, which bind in the DNA major groove, the new complexes show an unusual reactivity on DNA: they are the first platinum complexes capable of binding to N3 of adenine in the minor groove, based on an intercalator (acridine) mediated minor-groove association at adenine-containing base-pair steps. In non-small cell lung cancer cells the platinum-acridine complex showed a p53-independent cell-kill mechanism, which is also a unique feature within the series of non-classical platinum drugs.

With these high class contributions from leading experts, we are convinced to cover the latest understanding of the mechanism of action of tumor-inhibiting platinum complexes and to present very recent strategies in the design of novel and innovative anticancer platinum agents. The fight against cancer is ultimately our major concern and we hope that this theme issue will act as stimulus for future developments in this exciting field of research at the edge of inorganic chemistry and medicine. Finally, I would like to express my sincere gratitude to all my colleagues for generously contributing their time and expertise to this hot topic issue.

Markus Galanski
Institute of Inorganic Chemistry
University of Vienna
Vienna
Austria

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Biochemical Mechanisms of Cisplatin Cytotoxicity
V. Cepeda, M.A. Fuertes, J. Castilla, C. Alonso, C. Quevedo and J.M. Pérez

[Full text article]

Since the discovery by Rosenberg and collaborators of the antitumor activity of cisplatin 35 years ago, three platinum antitumor drugs (cisplatin, carboplatin and oxaliplatin) have enjoyed a huge clinical and commercial hit. Ever since the initial discovery of the anticancer activity of cisplatin, major efforts have been devoted to elucidate the biochemical mechanisms of antitumor activity of cisplatin in order to be able to rationally design novel platinum based drugs with superior pharmacological profiles. In this report we attempt to provide a current picture of the known facts pertaining to the mechanism of action of the drug, including those involved in drug uptake, DNA damage signals transduction, and cell death through apoptosis or necrosis. A deep knowledge of the biochemical mechanisms, which are triggered in the tumor cell in response to cisplatin injury not only may lead to the design of more efficient platinum antitumor drugs but also may provide new therapeutic strategies based on the biochemical modulation of cisplatin activity.

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The Role of Sulfur in Platinum Anticancer Chemotherapy
X. Wang and Z. Guo

[Full text article]

Sulfur manifests its influence on platinum anticancer chemotherapy in two aspects: endogenous sulfur-containing molecules such as cysteine, methionine, glutathione, metallothionein and albumin affect the metabolism of platinum drugs and exert adverse effects on the therapeutic efficacy; exogenous congeners such as amifostine (WR-2721) and dimesna (BNP7787) mitigate the toxic side effects of platinum drugs and serve as chemoprotectants. The platinum-sulfur interactions are ubiquitous in the human body and many occurrences encountered during platinum chemotherapy such as uptake, excretion, resistance, and toxicity are related to them. Thus, sulfur-containing molecules play significant roles in the anticancer mechanism of platinum drugs. In this review, the platinum-sulfur interactions are summarized in detail, which may be important for efficient clinical use of the existing platinum agents and beneficial to the rational design of new generation of platinum-based anticancer drugs.

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NMR Spectroscopy of Anticancer Platinum Drugs
J. Vinje and E. Sletten

[Full text article]

The focus of this review is on recently published papers (2000-2005) where NMR spectroscopy has been applied as the principal method in the study of anticancer platinum drugs. The paper gives an overview of the basic NMR techniques particularly relevant for studying interaction between platinum compounds and nucleic acid constituents. The latest NMR studies on the well-known anticancer drug cisplatin, with focus on kinetics and cisplatin-DNA structures are reported. Also cisplatin analogues clinically approved or currently in clinical trials are discussed. In addition two new classes of anticancer platinum drugs are described: trans-oriented Pt iminoether complexes and multinuclear Pt complexes. Reaction kinetics and structural changes induced by these novel Pt drugs are discussed in relation to cisplatin. NMR studies of non-DNA platinum drug targets including peptides, proteins and phospholipid membranes are also treated.

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Searching for the Magic Bullet: Anticancer Platinum Drugs Which Can Be Accumulated or Activated in the Tumor Tissue
M. Galanski and B.K. Keppler

[Full text article]

Cisplatin, carboplatin and oxaliplatin are anticancer drugs, which are efficiently used in the clinics all over the world. Besides a remarkable therapeutic efficacy in a series of solid tumors and outstanding activity of cisplatin against testicular germ-cell cancer, the platinum-based therapy is in part accompanied by a set of severe toxic side-effects. The design of platinum complexes being equipped with an exclusive selectivity for the tumoral tissue and exhibiting a lack of systemic toxicity (‘magic bullets’) is the great hope in the fight against cancer and also a motor within the expanding field of bioinorganic chemistry. In this review article, two promising strategies, namely accumulation and activation of tumor inhibiting platinum complexes specifically at the tumor site is presented, demonstrating a stepwise approach towards the ‘magic bullet’ concept propagated by Paul Ehrlich.

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Photoactivatable Platinum Complexes
P.J. Bednarski, F.S. Mackay and P.J. Sadler

[Full text article]

The development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and hence lowering toxicity of this important class of antitumor drugs. These drugs could find use in treating localized tumors accessible to laser-based fiber-optic devices. Pt^IV complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the Pt^II species to become cytotoxic. Based on the knowledge of Pt^IV photochemistry, Pt^IV analogs of cisplatin, [Pt(en)Cl2] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic Pt^II species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-Pt^IV and diazido-Pt^IV diam(m)ine complexes. The first generation, diiodo-Pt^IV complexes, represented by cis, trans-[Pt(en)(I)₂(OAc)₂], react to visible light by binding irreversibly to DNA and forming adducts with 5'-GMP in the same manner as [Pt(en)Cl₂]. Furthermore, the photolysis products are cytotoxic to human cancer cells in vitro. However, these complexes are too reactive towards biological thiols (i.e., glutathione), which rapidly reduced them to cytotoxic PtII species, thus making them unsuitable as drugs. The second generation, diazido-PtIV complexes, represented by cis, trans, cis-[Pt(N₃)₂(OH)₂(NH₃)₂] and cis, trans-[Pt(en)(N₃)₂(OH)₂], are also photosensitive, binding irreversibly to DNA and forming similar products with DNA and 5'-GMP in the presence of light as the respective Pt^II complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of λ_irr = 366 nm activates both complexes to cytotoxic species that effectively kill cancer cells by destroying their nuclei, leaving behind shrunken cell ghosts. Interestingly, the all-trans analog, trans, trans, trans-[Pt(N₃)₂(OH)₂(NH₃)₂] is non-toxic to HaCaT keratinocytes in the dark, but as active as cisplatin in the light. These studies show that photoactivatable Pt^IV antitumor agents represent a promising area for new drug development.

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Preclinical and Clinical Studies on the Use of Platinum Complexes for Breast Cancer Treatment
I. Ott and R. Gust

[Full text article]

Platinum complexes such as cisplatin and carboplatin are widely used in todays cancer chemotherapy but not in the present therapy of breast cancer, the most frequent epithelial malignancy among women.

As platinum compounds display high antitumoral efficacy against several breast cancer cell lines in-vitro they may be an interesting option for future clinical therapy of this disease. On the preclinical stage hormonally active and tissue selective platinum anticancer drugs have been investigated. Clinical trials on established platinum drugs (mainly cisplatin and carboplatin) showed that they can be efficient cytostatics for breast cancer therapy, if patients are carefully selected and suitable combination regimens (e.g. including taxanes) are administered. This review covers the latest findings about new platinum complexes in preclinical studies on the use against breast cancer as well as the outcome of the most relevant clinical trials.

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Trans-Platinum Complexes in Cancer Therapy
M. Coluccia and G. Natile

[Full text article]

The research of new platinum drugs active towards cisplatin refractory/resistant tumors has been mostly focussed on compounds with cis geometry because transplatin, the trans-isomer of cisplatin, is inactive. It is widely accepted that transplatin inactivity stems from two major factors: i) the kinetic instability promoting its deactivation and ii) the formation of DNA adducts characterized by a regioselectivity and a stereochemistry different from those of cisplatin. However, several exceptions to the general rule that the presence of two leaving groups in cis positions is necessary for antitumor activity of platinum complexes, have been reported. Substitution of transplatin ammine ligands by aromatic N-donor heterocycles, branched aliphatic amines, or imino ligands has lead to compounds with relevant in vitro tumor cell growth inhibitory potency, often active towards cisplatin refractory/resistant tumor cells, and in some cases endowed with significant activity also in vivo. From a mechanistic point of view, substitution of bulky ligands for ammines can retard substitution of the two chloride ligands, thus reducing the kinetic instability of the trans-platinum compounds. On the other hand, the formation of DNA adducts qualitatively and quantitatively different from those of cisplatin strongly supports the hypothesis that antitumor-active trans-platinum complexes can have a different spectrum of activity. It is hoped that the increasing knowledge of the biochemical and cellular processes underlying the antitumor-activity of trans-platinum complexes will foster their clinical development.

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Adenine-N3 in the DNA Minor Groove - An Emerging Target for Platinum Containing Anticancer Pharmacophores
R. Guddneppanavar and U. Bierbach

[Full text article]

The minor-groove is an important receptor for enzymes and proteins involved in the processing and expression of genomic DNA. Small molecules capable of interfering with these processes by virtue of their ability to form adducts within the recognition sequences targeted by these enzymes/proteins have potential applications as cytotoxic and gene-regulating agents. Until recently, the targeting of the minor groove by platinum-based agents has been a widely unexplored opportunity. As part of this focused review on irreversible minor-groove modifying agents acting on adenine-N3, we summarize work performed in our laboratory and by our collaborators on a novel platinum–acridine conjugate, PT-ACRAMTU ([PtCl(en)(ACRAMTU)](NO₃)₂, en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea, acridinium cation). The design of this agent as a non-cisplatin type pharmacophore has led to a ground-breaking discovery, the unprecedented intercalator-driven formation of platinum–adenine-N3 adducts in the minor groove of DNA. The minor-groove reactivity of PT-ACRAMTU represents a new paradigm in platinum–DNA interactions, which opens new avenues in the design of platinum-based therapeutics acting by a mechanism different from that of agents currently in clinical use.