Screening of microbial products led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both; cause DNA strand scission; and interfere with cell replication. All of the anti-cancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin.
The anthracycline antibiotics, isolated from Streptomyces peucetius var caesius, are among the most widely used cytotoxic anti-cancer drugs. The structures of the two original anthracyclines, doxorubicin and daunorubicin, are shown below. Several other anthracycline analogs have entered clinical practice, including idarubicin, epirubicin, and mitoxantrone. The anthracyclines exert their cytotoxic action through four major mechanisms: (1) inhibition of topoisomerase II; (2) generation of semiquinone free radicals and oxygen free radicals through an iron-dependent, enzyme-mediated reductive process; (3) high-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand scission; and (4) binding to cellular membranes to alter fluidity and ion transport. While the precise mechanisms by which the anthracyclines exert their cytotoxic effects remain to be defined in particular tumors, the free radical mechanism is well-established to be the cause of the cardiotoxicity associated with the anthracyclines (Table 54–4).
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Anthracyclines are administered via the intravenous route. They are metabolized extensively in the liver, with reduction and hydrolysis of the ring substituents. The hydroxylated metabolite is an active species, whereas the aglycone is inactive. Up to 50% of drug is eliminated in the feces via biliary excretion, and dose reduction is required in patients with liver dysfunction. Although anthracyclines are usually administered on an every-3-week schedule, alternative schedules such as low-dose weekly or 72to 96-hour continuous infusions have been shown to yield equivalent clinical efficacy with reduced toxicity.
Doxorubicin is one of the most important anti-cancer drugs in clinical practice, with major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas; and in several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. It also has clinical activity in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and Hodgkin’s and non-Hodgkin’s lymphomas. It is generally used in combination with other anti-cancer agents (eg, cyclophosphamide, cisplatin, and 5-FU), and clinical activity is improved with combination regimens as opposed to single-agent therapy.
Daunorubicin was the first agent in this class to be isolated, and it is still used in the treatment of acute myeloid leukemia. In contrast to doxorubicin, its efficacy in solid tumors is limited.
Idarubicin is a semisynthetic anthracycline glycoside analog of daunorubicin, and it is approved for use in combination with cytarabine for induction therapy of acute myeloid leukemia. When combined with cytarabine, idarubicin appears to be more active than daunorubicin in producing complete remissions and in improving survival in patients with acute myelogenous leukemia.