Cisplatin alkylating agent

Cisplatin Alkylating agent—crosslinks DNA strands Testicular, ovarian, bladder, lung CA Nausea, vomiting (use ondansetron) Nephrotoxicity (use amifostine) Neurotoxicity (deafness)... 

Cisplatin was discovered fortuitously by observing that bacteria present in electrolysis solutions could not divide. It is hypothesized that in the intracellular environment, a chloride is lost and replaced by a water molecule. The resulting species is an efficient bifunctional interactor with DNA, forming platinum-based cross-links similar to that formed by alkylating agents. 

Cisplatin administration requires adequate hydration and forced diuresis to prevent kidney damage. Cisplatin is intensely emetogenic and its use requires adequate antiemetic prophylaxis. Myelosuppression is less evident than with other alkylating agents. 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

The antidote of choice for mechlorethamine extravasations is sodium thiosulfate. This agent binds alkylating agents, resulting in neutralization to inactive compounds that are then excreted. Sodium thiosulfate also may be effective for high-concentration cisplatin or dacarbazine extravasations. 

Alkylating agents Nitrogen mustards (cyclophosphamide) Busulphan Platinum coordination complexes (cisplatin) Nitrosoureas Crosshnks DNA strands... 

Alkylating agents are compounds capable of reacting covalently with DNA bases. If a compound of this type contains two reactive groups, intramolecular or intermolecular crosslinking of the DNA double helix and bending of the double strand occurs. Examples of this type shown here are cyclophosphamide and the inorganic complex cisplatin. Anthracyclines such as doxorubicin (adriamy-cin) insert themselves non-covalently between the bases and thus lead to local alterations in the DNA structure (see p. 254 B). 

Possible biochemical mechanisms of resistance to alkylating agents include changes in ceU DNA repair capability, increases in cell thiol content (which in turn can serve as alternative and benign targets of alkylation), decreases in ceU permeability, and increased activity of glutathione transferases. Increased metaUothionein content has been associated with tumor cell resistance to cisplatin. 

Heavy metal compounds used to treat cancer include cisplatin, carboplatin, and oxaliplatin (see Table 36-6). These drugs, which contain platinum, are also known as platinum coordination complexes.10,27 Heavy metal drugs act like the alkylating agents that is, they form strong cross-links between and within DNA strands,... 

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, several studies have shown that carboplatin and paclitaxel yields clinical results similar to what is achieved with the cisplatin plus paclitaxel combination however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy. 

Compared to other solid tumors, ovarian cancer is relatively responsive to chemotherapy, but unlike testicular cancer, cure is not common for patients with advanced disease. Prior to the incorporation of cisplatin or carboplatin into treatment regimens, chemotherapy for advanced-stage ovarian cancer consisted of combinations of alkylating agents and doxorubicin. Response rates from such regimens were of the order of 33-65%, and fewer than 10% of patients survived 5 years [51]. 

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