Antitumor Antibiotics and Related Synethetic Compounds

Most of the antitumor antibiotics were initially isolated from various Streptomyces species. Central to their cytotoxic profile is the presence of numerous mechanisms by which each individual antibiotic interacts with DNA. The variety of chemical structures present in each compound participate in multiple mechanisms responsible for their activity against cells. The polycyclic chromophore structure intercalates with DNA and is also responsible for conferring the characteristic bright color of these drugs. Ring structures, such as the quinone group, not only interfere with electron transport, but also bind metal cations, intercalate into DNA and RNA, and generate reactive oxidant species, to name a few actions. DNA-modifying enzymes, such as topoisomerases and heli-cases, are common cellular enzymes targeted by these drugs.

Dose-limiting toxicities are related to myelosuppression and mucositis. Variable susceptibility to congestive car-diomyopathy is an associated complication from cumulative dose administration of anthracyclines. Emetogenic potential is considerable. Reversible alopecia is not unusual. They are also among the most potent vesicants available, and thus scrupulous attention should be given during the administration of these agents to prevent tissue extravasation. Photo-sensitivity, hyperpigmentation, and pigmentation of the nails and urine are common. Another interesting toxicity is the radiation recall phenomenon. As the term suggests, pain, erythema, and blistering or ulceration occur on previous radiation sites within 3 to 7 days of administration of the antitumor antibiotic. This phenomenon may be observed on any epithelial surface and may thus manifest as dermatitis, enteritis, pneumonitis, or stomatitis. The drugs most commonly implicated are the anthracyclines doxorubicin and daunorubicin, dactinomycin, and bleomycin.

Anthracyclines

The anthracyclines doxorubicin and daunorubicin are commonly incorporated into standard therapy regimens for multiple cancer types, given their broad antitumor activity over a wide range of doses and administration schedules as well as the lack of antagonistic interactions with other commonly used chemotherapy agents.

Anthracyclines exert pleiotropic mechanisms by which they effect cytotoxicity. Aside from DNA intercalation, anthracyclines inhibit DNA topoisomerase II, an enzyme that releases the torsional strain in DNA by actively inserting stable DNA strand breaks, facilitating the passage of one of the DNA strands through the other in the helix and then rean-nealing the strand break.55 Anthracyclines form a ternary 'cleavable complex' with DNA topoisomerase II, which then 'traps' the DNA strand passage intermediates. This inhibition of topoisomerase II can be detected as protein-associated DNA single- and double-strand breaks linked to the enzyme. Another target is a group of nuclear enzymes, the helicases, that is critical in duplex DNA dissociation into single strands.56 Their anthraquinone structure enables them to undergo one-electron reduction reactions catalyzed by flavin dehydrogenases or reductases. These reactions generate free radicals and other reactive oxidant species that damage intra-cellular macromolecules.57 Moreover, certain signal transduction pathways, such as protein kinase C and the sphingomyelin pathway, can be modulated by anthracyclines, the end effects of which include apoptosis.58,59

Doxorubicin

Doxorubicin is primarily hepatically metabolized. The lipo-somal formulation has a small volume of distribution and hence is mainly confined to the intravascular compartment. It has a slower plasma clearance and prolonged terminal halflife compared to the regular formulation. Doxorubicin can induce histamine release, manifesting as facial flushing. Atrial and ventricular dysrhythmia may arise acutely with anthracycline administration, although these are usually not life threatening. Congestive cardiomyopathy is a late complication, occurring at less than 5% with cumulative dosage of greater than 400 mg/m2 with intermittent schedules, 550 mg/m2 with weekly, or up to 800 to 1,000 mg/m2 with continuous infusion schedules. Risk factors that predispose to earlier development of congestive heart failure are old age; cardiovascular disorder associated with increased left ventricular outflow tract gradients, such as uncontrolled hypertension, aortic stenosis, or underlying cardiomyop-athy; history of congestive heart disease; and mediastinal irradiation.

Epirubicin

Epirubicin is a derivative of doxorubicin. It is hepatically glu-curonidated and its metabolites are excreted in bile. It was developed in efforts to reduce cardiotoxicity seen with dox-orubicin. Epirubicin has a more favorable therapeutic index, with 30% less hematologic toxicity at equimolar doses. Risk of congestive heart failure, which may not differ from dox-orubicin at equimyelosuppressive doses,60 increases significantly with cumulative doses greater than 900 mg/m2. Similar to doxorubicin, continuous infusion and weekly schedules are associated with decreased risk of cardiotoxicity. Epirubicin is used as a component of regimens used in adjuvant therapy in breast and gastric cancer.

Daunorubicin

Daunorubicin was the prototype anthracycline studied in the 1960s. It is more lipid soluble than doxorubicin, owing to the absence of one hydroxyl group. As compared to doxorubicin, there is a lower incidence of mucositis and colonic perforation. The renal clearance is approximately twice that for dox-orubicin, thus making dose adjustments in patients with hepatic dysfunction unnecessary in many situations. Cardiac toxicity is likewise limiting. Its current use is mainly in the remission induction regimens for acute leukemias.

Idarubicin

Idarubicin is a 4-demethoxy derivative of daunorubicin that is orally bioavailable, has a longer half-life, and less potential for cardiotoxicity. Because of the alteration in its ring structure, it has a yellow color in aqueous solutions, as opposed to the characteristic red color of doxorubicin and daunorubicin. The primary metabolite of idarubicin, 13-idarubicinol, is cytotoxic and largely renally excreted. Although it has significant activity in the treatment of acute myelogenous leukemia (AML), it is less active against solid tumors.

Anthracenediones

Mitoxantrone

Mitoxantrone, a dark blue anthracenedione originally synthesized as a stable dye, intercalates nucleic acids and thus inhibits DNA and RNA synthesis. It also inhibits topoisom-erase II by the formation of a cleavable complex, thus causing protein-associated single-strand DNA breaks.61 In spite of its quinone structure, free radical production is limited, and in one model, mitoxantrone inhibited the rate of lipid peroxidation induced by doxorubicin.62 This is clinically observed in the reduced severity of its cardiac effects in contrast to doxorubicin. It is used mainly in prostate and breast cancers, as well as leukemias and lymphomas.

Bleomycin

Bleomycin is a cell-cycle-specific polypeptide antibiotic that requires a metal ion cofactor for its activity, such as copper or iron, without which single- and double-strand breaks (approximately 10:1) in DNA cannot be produced.63 Inhibition of cell growth occurs at the S phase, although it can also induce a G2 arrest.64 It is a mixture of multiple glycopeptides, the predominant active component of which is the A2 peptide, comprising 70% of the commercial preparation.

Bleomycin has a short half-life.65 Renal excretion is the primary route of eliminating up to 70% of unchanged drug after a given dose. It is inactivated in the tissues by the enzyme bleomycin hydrolase, the concentrations of which are lowest in skin and lung,66 thus explaining the clinical tox-icities encountered. Fever within the first 12 hours of administration is almost universally observed. Hypotension is seen with rapid intravenous infusions of higher doses. Anaphylac-toid reactions have been described, mostly in lymphoma patients receiving their first dose.67 The most feared complication, however, is pulmonary interstitial fibrosis, which appears to be cumulatively dose dependent at 300 units total dose.66 Pulmonary fibrosis appears earlier in those with impaired renal function. Exposure to high oxygen tensions even after prior therapy with bleomycin is associated with increased risk of developing this pulmonary toxicity. Onset is unpredictable, as it may occur during treatment or after cessation of therapy, and may progress even after discontinuation of the drug.68 It is used in curative regimens for testic-ular cancer and Hodgkin's lymphoma.

Dactinomycin (Actinomycin D) Actinomycin D has a tricyclic phenoxazone ring, which imparts its yellow color, attached to two symmetric cyclic polypeptides. It binds DNA, and also inhibits RNA and protein synthesis, by intercalating DNA through its chromophore structure between base pairs, whereas the peptide lactone rings lie in the minor groove of DNA.69 Its rapid tissue uptake and long terminal half-life permit intermittent administration. The radiation recall phenomenon was first described in patients who received actinomycin, even years after irradiation. Toxic-ities are similar to the other antitumor antibiotics and seem to be of greater severity. It is used in curative regimens for several childhood tumors, refractory germ cell tumors.

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