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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Alkylating Agents
Classification: Platinum Analogs:
Platinum agents describe an important group of anticancer drugs.16
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Identification of anticancer effects associated with platinum compounds was dependent on experiments by Dr. Barnett Rosenberg who was examining electrical currents and their effects on bacterial growth.16
Dr. Rosenberg noted that the electric field induced or apparently induced morphological change in the bacteria.
However, control experiments indicated that this effect was not associated directly with the electric field but rather by products produced by platinum electrodes.
Analysis of these products identified a platinum coordination complex as the responsible agent with respect to bacterial change.
Platinum compounds showed antitumor activity in a variety of tumor models.
Of these tumors, testicular cancer appeared particularly sensitive and with prehydration, otherwise significant toxicities could be mitigated.
As a result of Prof. Rosenberg's
experiments on "electric fields", a new group of anticancer agents was
discovered and cisplatin is considered curative not only in testicular
cancer but also prolongs survival when cisplatin is combined with other
anticancer agents in cases of other malignancies including ovarian, head and
neck cancer, lung cancer, bladder cancer, and upper G.I. cancer.16
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These agents can be used alone or in combination with other anticancer agents.
Cisplatin (Platinol, cis-diamminedichloroplatinum (II)) and related agents have improved the treatment of many solid tumors for over four decades.
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Platinum analogues have been developed that exhibit both reduced toxicity and more activity targeting various tumor types.
Some tumor types so targeted by platinum analogues had previously developed resistance to cisplatin.
Although in the United States cisplatin has led to two additional platinum analogues that have been approved: carboplatin (Paraplatin) and oxaliplatin (Eloxatin), other analogues have been developed elsewhere e.g. lobaplatin (China) and nedaplatin (Japan).16
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Although precise mechanisms of action of platinum analogs remain to be determined, cytotoxic activity follows that described for alkylating agents.3
Tumor cells cytotoxicity is associated with all cell cycle stages as a result of drug-mediated DNA intrastrand and interstrand cross-links.
These linkages inhibit both DNA synthesis and function. Multiple DNA linkage sites identified with platinum analogs include guanine (N7), adenine (N3) and cytosine (O6).
Whereas the primary platinum analogue target appears to be DNA, other binding sites have been identified.
For example, these agents bind to both nucleoproteins and cytoplasmic proteins in such binding may be involved in antitumor actions.3
Entry into cells by the platinum anticancer drugs is facilitated by the Cu2+ transporter system, CTR1.
Platinum compounds are extruded from cells by specific copper exporters such as ATP7A (a.k.a. Menkes’ protein, utilizing P-type ATPase coupling) and ATP7B (encoded by the ATP7B gene, localized in trans-Golgi networks) is as well as by MRP1 (Multidrug Resistance-Associated Protein 1.17
Clinical resistance to the action of platinum anticancer drugs may be explained in part by changes in expression of transporters responsible for both transporting the drug into the cell as well as extruding the drug.
Inside the cell, platinum anticancer drugs must be activated through a process that involves displacement by water molecules of drug analog ligands, such as chloride.
As a result, positively charged platinum analogues are reactive at nucleophilic DNA and proteins sites.
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