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Chapter: Modern Pharmacology with Clinical Applications: Antineoplastic Agents

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Antineoplastic Agents: Miscellaneous Agents

Hydroxyurea (Hydrea) inhibits the enzyme ribonu-cleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impair-ment of DNA synthesis.

MISCELLANEOUS AGENTS

 

 

Hydroxyurea

 

Hydroxyurea (Hydrea) inhibits the enzyme ribonu-cleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impair-ment of DNA synthesis. The drug therefore is an S-phase specific agent whose action results in an accumu-lation of cells in the late G1- and early S-phases of the cell cycle.

 

Hydroxyurea is rapidly absorbed after oral adminis-tration, with peak plasma levels achieved approxi-mately 1 to 2 hours after drug administration; its elimination half-life is 2 to 3 hours. The primary route of ex-cretion is renal, with 30 to 40% of a dose excreted un-changed.

 

Hydroxyurea is used for the rapid lowering of blood granulocyte counts in patients with chronic granulocytic leukemia. The drug also can be used as maintenance therapy for patients with the disease who have become resistant to busulfan. Only a small percentage of pa-tients with other malignancies have had even brief re-missions induced by hydroxyurea administration.

 

Hematological toxicity, with white blood cells af-fected more than platelets, may occur. Megaloblastosis of the bone marrow also may be observed. Recovery is rapid, generally within 10 to 14 days after discontinua-tion of the drug. Some skin reactions, including hyper-pigmentation and hyperkeratosis, have been reported with chronic treatment.

 

Procarbazine

 

Procarbazine (Matulane) may autooxidize sponta-neously, and during this reaction hydrogen peroxide and hydroxyl free radicals are generated. These highly reactive products may degrade DNA and serve as one mechanism of procarbazine-induced cytotoxicity. Cell toxicity also may be the result of a transmethylation re-action that can occur between the N-methyl group of procarbazine and the N7 position of guanine.

 

Procarbazine is rapidly absorbed after oral adminis-tration and has a plasma half-life of only 10 minutes. The drug crosses the blood-brain barrier, reaching lev-els in CSF equal to those obtained in plasma. Metabolism is extensive and complex. Urinary excre-tion accounts for 70% of the procarbazine and its metabolites lost during the first 24 hours after drug ad-ministration.

 

When originally tested as a single agent in advanced Hodgkin’s disease, procarbazine produced tumor re-gression responses that were brief, usually lasting only 1 to 3 months. The combination of procarbazine with mechlorethamine, vincristine, and prednisone in the MOPP regimen, however, resulted in an 81% complete remission rate in Hodgkin’s disease. Most of these pa-tients are considered cured. Procarbazine is also used in various combination chemotherapy protocols for non-Hodgkin’s lymphomas and small cell anaplastic (oat cell) carcinoma of the lung. Limited antitumor effects have been observed against multiple myeloma, melanoma, and non–oat cell lung cancers.

 

The major side effects associated with procarbazine therapy are nausea and vomiting, leukopenia, and throm-bocytopenia. Skin rashes have been reported, as have rare cases of allergic interstitial pneumonia. Procar-bazine administration produces a high degree of chro-mosomal breakage, and the compound is mutagenic, ter-atogenic, and carcinogenic in experimental systems.

Procarbazine may potentiate the effects of tranquil-izers and hypnotics. Hypertensive episodes can result if procarbazine is administered simultaneously with adrenomimetic drugs or with tyramine-containing foods. Rarely, a reaction to alcohol similar to that pro-voked by disulfiram may occur.

 

Mitotane

 

The observation that mitotane (Lysodren) could pro-duce adrenocortical necrosis in animals led to its use in the palliation of inoperable adrenocortical adenocarci-nomas. A reduction in both tumor size and adrenocorti-cal hormone secretion can be achieved in about half of the patients taking the drug. Because normal adreno-cortical cells also are affected, endogenous glucocorti-coid production should be monitored and replacement therapy administered when appropriate.

 

Mitotane is incompletely absorbed from the gas-trointestinal tract after oral administration. However, once absorbed, it tends to accumulate in adipose tissue. Mitotane is slowly excreted and will appear in the urine for several years. The major toxicities associated with its use are anorexia, nausea, diarrhea, lethargy, somno-lence, dizziness, and dermatitis.

 

Hexamethylmelamine

 

Although both DNA and RNA synthesis are inhibited in cells exposed to hexamethylmelamine (Hexalen), the molecular mechanisms of these effects are not known.

 

Hexamethylmelamine is readily absorbed after oral administration, with peak plasma levels achieved after 1 hour. The drug is readily metabolized to form a number of demethylated metabolites. Urinary elimination is the primary route of drug excretion.

 

Hexamethylmelamine is useful for the treatment of ovarian adenocarcinoma and is frequently combined with cyclophosphamide, cisplatin, and doxorubicin in the treatment of this tumor. It also has some activity against small cell lung cancer.

 

Nausea and vomiting are the major toxicities associ-ated with hexamethylmelamine administration. Myelo-suppression and a peripheral neuropathy also may occur.

 

 

Cisplatin

 

Cisplatin (Platinol) is an inorganic coordination com-plex with a broad range of antitumor activity. It is espe-cially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and O6 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferen-tially cross-linked. This platinating activity is analogous to the mode of action of alkylating agents. Cisplatin also binds extensively to proteins. It does not appear to be phase specific in the cell cycle.

 

Cisplatin shows biphasic plasma decay with a distri-bution phase half-life of 25 to 49 minutes and an elimi-nation half-life of 2 to 4 days. More than 90% of the drug is bound to plasma proteins, and binding may ap-proach 100% during prolonged infusion. Cisplatin does not cross the blood-brain barrier. Excretion is predom-inantly renal and is incomplete.

 

Cisplatin, combined with bleomycin and vinblastine or etoposide, produces cures in most patients with metastatic testicular cancer or germ cell cancer of the ovary. Cisplatin also shows some activity against carci-nomas of the head and neck, bladder, cervix, prostate, and lung.

 

Renal toxicity is the major potential toxicity of cisplatin. Severe nausea and vomiting that often accom-pany cisplatin administration may necessitate hospital-ization. Cisplatin has mild bone marrow toxicity, yield-ing both leukopenia and thrombocytopenia. Anemia is common and may require transfusions of red blood cells. Anaphylactic allergic reactions have been de-scribed. Hearing loss in the high frequencies (4000 Hz) may occur in 10 to 30% of patients. Other reported tox-icities include peripheral neuropathies with paresthe-sias, leg weakness, and tremors. Excessive urinary ex-cretion of magnesium also may occur.

 

Carboplatin

 

Carboplatin (Paraplatin) is an analogue of cisplatin. Its plasma half-life is 3 to 5 hours, and it has no significant protein binding. Renal excretion is the major route of drug elimination.

 

Despite its lower chemical reactivity, carboplatin has antitumor activity that is similar to that of cisplatin against ovarian carcinomas, small cell lung cancers, and germ cell cancers of the testis. Most tumors that are resistant to cisplatin are cross-resistant to carbo-platin.

 

The major advantage of carboplatin over cisplatin is a markedly reduced risk of toxicity to the kidneys, pe-ripheral nerves, and hearing; additionally, it produces less nausea and vomiting. It is, however, more myelo-suppressive than cisplatin. Other adverse effects include anemia, abnormal liver function tests, and occasional al-lergic reactions.

Mitoxantrone

 

Mitoxantrone (Novantrone) is a synthetic anthraquinone that is structurally and mechanistically related to the an-thracyclines. It intercalates with DNA and produces sin-gle-strand DNA breakage. It is cross-resistant with dox-

orubicin in multidrug-resistant cells and in patients who have failed to respond to doxorubicin therapy.

 

Mitoxantrone is active against breast carcinomas, leukemias, and lymphomas. Its antitumor efficacy in pa-tients with breast cancer is slightly lower than that of doxorubicin. Its major toxicity is myelosuppression; mu-cositis and diarrhea also may occur. Mitoxantrone pro-duces less nausea, alopecia, and cardiac toxicity than does doxorubicin.

 

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