Antineoplastic Agents: Antibiotics

ANTIBIOTICS

Doxorubicin and Daunorubicin

The anthracycline antibiotics are fermentation products of Streptomyces peucetius. Daunorubicin (Cerubidine) is used to treat acute leukemias, while its structural ana-logue, doxorubicin (Adriamycin) is extensively em-ployed against a broad spectrum of cancers. Although the two drugs have similar pharmacological and toxico-logical properties, doxorubicin is more potent against most animal and human tumors and will be discussed in greater detail.

Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is prefer-entially concentrated in nuclear structures. Inter-calation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The en-zyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracyclines. Cells in S-phase are most sensitive to doxorubicin, al-though cytotoxicity also occurs in other phases of the cell cycle.

In addition to the intercalation mechanism de-scribed, the anthracycline ring of doxorubicin can un-dergo a one-electron reduction to form free radicals and participate in further electron transfer. These highly active substances can then react with tissue macromol-ecules. This type of interaction suggests an alternative mechanism of cytotoxicity for the anthracyclines. In particular, the cardiac toxicity of anthracyclines may re-sult from the generation of free radicals of oxygen.

Resistance to the anthracyclines usually involves de-creased drug accumulation due to enhanced active efflux of drug. This form of drug resistance is common among the large, heterocyclic naturally derived anticancer agents. It is termed multidrug resistance because of the high degree of cross-resistance among the anthracy-clines, vinca alkaloids, dactinomycin, and podophyllo-toxins .

Doxorubicin is not absorbed orally, and because of its ability to cause tissue necrosis must not be injected intramuscularly or subcutaneously. Distribution studies indicate rapid uptake in all tissues except the CNS. Extensive tissue binding, primarily intranuclear, ac-counts for the prolonged elimination half-life. The drug is extensively metabolized in the liver to hydroxylated and conjugated metabolites and to aglycones that are primarily excreted in the bile.

Doxorubicin is one of the most effective agents used in the treatment of carcinomas of the breast, ovary, en-dometrium, bladder, and thyroid and in oat cell cancer of the lung. It is included in several combination regi-mens for diffuse lymphomas and Hodgkin’s disease. Doxorubicin can be used as an alternative to daunoru-bicin in acute leukemias and is useful in Ewing’s sar-coma, osteogenic sarcoma, soft-tissue sarcomas, and neuroblastoma. Some activity has been reported in non–oat cell lung cancer, multiple myeloma, and adeno-carcinomas of the stomach, prostate, and testis.

The most important toxicities caused by doxoru-bicin involve the heart and bone marrow. Acutely, doxo-rubicin may cause transient cardiac arrhythmias and depression of myocardial function. Doxorubicin may cause radiation recall reactions, with flare-ups of der-matitis, stomatitis, or esophagitis that had been pro-duced previously by radiation therapy. Less severe tox-icities include phlebitis and sclerosis of veins used for injection, hyperpigmentation of nail beds and skin creases, and conjunctivitis. Because of its intense red color, doxorubicin will impart a reddish color to the urine for 1 or 2 days after administration.

Idarubicin

Idarubicin (Idamycin) differs from its parent com-pound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mecha-nisms of action and resistance are similar to those of doxorubicin and daunorubicin; however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabo-lism and biliary excretion. Adverse reactions of idaru-bicin are similar to those of its congeners.

Bleomycin

The bleomycins are a group of glycopeptides that are isolated from Streptomyces verticillus. The clinical preparation, bleomycin sulfate (Blenoxane), is a mix-ture of several components. Bleomycin binds to DNA, in part through an intercalation mechanism, without markedly altering the secondary structure of the nucleic acid. The drug produces both single- and double-strand scission and fragmentation of DNA. It is thought that the bleomycins, which are avid metal-chelating agents, form a bleomycin–Fe complex that can donate elec-trons to molecular oxygen, thus forming the superoxide and hydroxyl free radicals. It is these highly reactive in-termediates that attack DNA and produce DNA strand breakage and maximum cytotoxicity in the late G₂ and early M-phases of the cell cycle.

Bleomycin is poorly absorbed orally, but it can be given by various parenteral routes. Its plasma half-life is not affected by renal dysfunction as long as creatinine clearance is greater than 35 mL/minute.

Bleomycin hydrolase, which inactivates bleomycin, is an enzyme that is abundant in liver and kidney but virtually absent in lungs and skin; the latter two organs are the major targets of bleomycin toxicity. It is thought that bleomycin-induced dermal and pulmonary toxici-ties are related to the persistence of relatively high local concentrations of active drug.

Bleomycin, in combination with cisplatin or etopo-side, is important as part of the potentially curative combination chemotherapy of advanced testicular car-cinomas. Bleomycin is used in some standard regimens for the treatment of Hodgkin’s and non-Hodgkin’s lym-phomas, and it is useful against squamous cell carcino-mas of the head and neck, cervix, and skin.

A potentially fatal lung toxicity occurs in 10 to 20% of patients receiving bleomycin. Patients particularly at risk are those who are over 70 years of age and have had radiation therapy to the chest. Rarely, bleomycin also may cause allergic pneumonitis. Bleomycin skin toxicity is manifested by hyperpigmentation, erythe-matosus rashes, and thickening of the skin over the dorsum of the hands and at dermal pressure points, such as the elbows. Many patients develop a low-grade transient fever within 24 hours of receiving bleomycin. Less common adverse effects include mucositis, alope-cia, headache, nausea, and arteritis of the distal ex-tremities.

Mitomycin

Mitomycin (mitomycin C, Mitocin-C, Mutamycin) is an antibiotic that is derived from a species of Streptomyces. It is sometimes classified as an alkylating agent because it can covalently bind to and cross-link DNA. Mitomycin is thought to inhibit DNA synthesis through its ability to alkylate double-strand DNA and bring about interstrand cross-linking. There is evidence that enzymatic reduction by a reduced nicotinamide– adenine dinucleotide phosphate (NADPH) dependent reductase is necessary to activate the drug.

The drug is rapidly cleared from serum after intra-venous injection but is not distributed to the brain.

Mitomycin has limited palliative effects in carcino-mas of the stomach, pancreas, colon, breast, and cervix.

The major toxicity associated with mitomycin ther-apy is unpredictably long and cumulative myelosup-pression that affects both white blood cells and platelets. A syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure also has been described. Renal, hepatic, and pulmonary toxicity may occur. The drug is teratogenic and carcinogenic, and it can cause local blistering.

Dactinomycin

Dactinomycin (actinomycin D, Cosmegen) is one of a family of chromopeptides produced by Streptomyces. It is known to bind noncovalently to double-strand DNA by partial intercalation, inhibiting DNA-directed RNA synthesis. The drug is most toxic to proliferating cells, but it is not specific for any one phase of the cell cycle. Resistance to dactinomycin is caused by decreased abil-ity of tumor cells to take up and retain the drug, and it is associated with cross-resistance to vinca alkaloids, the anthracyclines, and certain other agents (multidrug re-sistance).

Dactinomycin is cleared rapidly from plasma, does not enter the brain, is not appreciably metabolized or protein bound, and is gradually excreted in both bile and urine. Virtually no drug is detected in CSF.

Dactinomycin is used in curative combined treat-ment of Wilms’ tumor, Ewing’s sarcoma, rhabdomyosar-coma, and gestational choriocarcinoma. It is active in testicular tumors, lymphomas, melanomas, and sarco-mas, although its use in most of these malignancies has been supplanted by other agents.

The major side effects of dactinomycin are severe nausea, vomiting, and myelosuppression. Mucositis, di-arrhea, alopecia, and radiation recall reactions may oc-cur. The drug is immunosuppressive and carcinogenic.

Plicamycin

Plicamycin (mithramycin, Mithracin) is one of the chro-momycin group of antibiotics produced by Streptomyces tanashiensis. Plicamycin binds to DNA and inhibits tran-scription. It also inhibits resorption of bone by os-teoblasts, thus lowering serum calcium levels.Very little is known about its distribution, metabolism, and excretion. Because of its severe toxicity, plicamycin has limited clin-ical utility. The major indication for plicamycin therapy is in the treatment of life-threatening hypercalcemia asso-ciated with malignancy. Plicamycin also can be used in the palliative therapy of metastatic testicular carcinoma when all other known active drugs have failed.