Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 7, Issue 1, 2007

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.

Sulfur manifests its influence on platinum anticancer chemotherapy in two aspects: endogenous sulfurcontaining 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 platinumsulfur 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.

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.

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.

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. PtIV complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the PtII species to become cytotoxic. Based on the knowledge of PtIV photochemistry, Pt IV analogs of cisplatin, [Pt(en)Cl2] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic PtII species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-PtIV and diazido-Pt IV diam(m)ine complexes. The first generation, diiodo-PtIV 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 PtII complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of lirr = 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 PtIV antitumor agents represent a promising area for new drug development.

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.

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 Ndonor 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 transplatinum complexes will foster their clinical development.

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 generegulating 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, PTACRAMTU ([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 groundbreaking 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.