Organoplatinum Compounds

There are several organometallic compounds based on platinum that play a central role in many cancer treatment protocols (Fig. 10.5). The first of these, cisplatin, was discovered by Barnett Rosenberg as a result of experiments investigating the role of electrical current on cell division. Escherichia coli cells in an ammonium chloride solution had an electrical current applied through platinum elec-trodes.22 It was subsequently found that cell division was inhibited but not as a result of the current but from the reaction of the ammonium chloride with what was thought to be an inert platinum electrode. Further investigation led to the identification of cis-[PtCl2(NH3)2] as the active species and mechanistic studies revealed that after administration of the agent to mammals, the dichloro species is maintained in the blood stream as a result of the relatively high chloride concentration (Scheme 10.10).23 Movement into the tumor cells is accomplished by passive diffusion or carrier-mediated transport. Once inside the tumor cell, the drug encounters a lower chloride concentration and one chloro group is substituted by a water molecule in a process known as aquation. This serves to "trap" the molecule in the cell as a result of ionization. Reaction with DNA occurs preferentially at the N-7 of guanine of two adjacent guanine residues resulting in primarily (95%) intrastrand cross-links.24

Platinum (II) is considered to be a "soft" electrophile and as a result, its complexes are subject to attack by "soft" nucleophiles such as thiol groups found on proteins. This can result in significant protein binding (88%-95%) and inactiva-tion caused by the presence of thiols in albumin, glutathione, and other proteins.25 Cisplatin administration is also associated with significant nephrotoxicity and neurotoxicity that is dose limiting. These factors lead to the development of less

Reduction Organo Platinum
DNA cross linking Scheme 10.7 • Metabolic and chemical activation of ifosfamide.

reactive platinum compounds such as carboplatin and oxali-platin in which the leaving group was incorporated into a chelate. More recently, there has been interest in the development of Pt(IV) compounds, which are much less reactive and believed to function as prodrugs requiring reduction to the Pt(II) species prior to reaction with nucleophiles. One such agent, satraplatin is currently in clinical trials. One advantage of these agents is the possibility of oral administration. Satraplatin has shown similar activity when given orally to that of cisplatin given by injection.

Tumor cells may become resistant to the platins by mechanisms that are seen with other chemotherapeutic agents such as decreased uptake, increased inactivation by thiol-containing proteins and increased DNA repair. However, a deficiency in a type of DNA repair known as mismatch repair (MMR) has also been implicated in resistance to cisplatin and carboplatin.26 The process of MMR involves several enzymes that are responsible for maintaining the integrity of the genome, and interest has focused on the interaction of these enzymes with repeating units found throughout DNA known as microsatellites. When MMR processes are not operating, these microsatellites may become longer or shorter and this is known as microsatellite instability. This can result in frame shift errors such that tumor suppressor genes may become less effective, and the tumor cells therefore fail to undergo apoptosis even if

Thiotepa Alkylation
Scheme 10.8 • Metabolic and chemical interactions of thiotepa with DNA.

alkylation has occurred. The binding of cisplatin- and carbo-platin-DNA adducts by the MMR enzymes results in increased cytotoxicity of these agents. Several rationales have been put forward as to why this occurs, including the involvement of MMR enzymes in downstream signaling that activates apoptosis. A second rationale involves the ability of MMR enzymes to remove replication errors that occur past the point of adduct formation, and in the process of removing these errors, gaps in the DNA are created, which lead to cell death. When there is a deficiency in the MMR enzymes, cells may be resistant to cisplatin and carboplatin because both of these agents produce the same DNA adduct.

Pharmaceutical Molecule

Tetrahydrothiophene-1 -oxide Sulfolane 3-Hydroxysulfolane

Scheme 10.9 • Metabolic and chemical reactions of busulfan.

Tetrahydrothiophene-1 -oxide Sulfolane 3-Hydroxysulfolane

Scheme 10.9 • Metabolic and chemical reactions of busulfan.

Figure 10.5 • Platinum-containing antineoplastics.

The bulkier oxaliplatin-DNA adduct does not seem to be recognized by the same enzymes and does not depend on MMR enzymes for its cytotoxicity, and several cell lines that are resistant to cisplatin and carboplatin are still susceptible to oxaliplatin. In addition, several DnA polymerases are unable to replicate past cisplatin-DNA adducts but are able to replicate past oxaliplatin-DNA adducts.27 This difference has been used to explain the greater mutagenicity that is seen with cisplatin compared with oxaliplatin. These two compounds both form primarily intrastrand links between adjacent guanine residues or adjacent guanine-adenine residues; however, nuclear magnetic resonance (NMR) analysis has recently shown that the amount of DNA bending is much greater, and the minor groove is widened for the cisplatinDNA adduct compared with the oxaliplatin-DNA adduct. The greater bending associated with cisplatin-DNA adducts is recognized by MMR enzymes possibly explaining the differential effects of cisplatin and oxaliplatin on these enzymes.

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