Antimetabolites are structural analogs of the naturally occurring metabolites involved in DNA and RNA synthesis. As the constituents of these metabolic pathways have been elucidated, a large number of structurally similar drugs that alter the critical pathways of nucleotide synthesis have been developed.
Antimetabolites exert their cytotoxic activity either by competing with normal metabolites for the catalytic or regulatory site of a key enzyme or by substituting for a metabolite that is normally incorporated into DNA and RNA. Because of this mechanism of action, antimetabolites are most active when cells are in the S phase and have little effect on cells in the G0 phase. Consequently, these drugs are most effective against tumors that have a high growth fraction.
Antimetabolites have a nonlinear dose-response curve, such that after a certain dose, no more cells are killed despite increasing doses (5-FU is an exception). The antimetabolites can be divided into folate analogs, purine analogs, adenosine analogs, pyrimidine analogs, and substituted urea.
A wide variety of compounds possessing antitumor activity have been isolated from natural substances, such as plants, fungi, and bacteria. Likewise, selected compounds have semisynthetic and synthetic designs based on the active chemical structure of the parent compounds, and they, too, have cytotoxic effects.
Antitumor antibiotics Bleomycin preferentially intercalates DNA at guanine-cytosine and guanine-thymine sequences, resulting in spontaneous oxidation and formation of free oxygen radicals that cause strand breakage.
Anthracyclines The anthracycline antibiotics are products of the fungus Streptomyces percetus var caesius. They are chemically similar, with a basic anthracycline structure containing a glycoside bound to an amino sugar, daunosamine. The anthracyclines have several modes of action. Most notable are intercalation between DNA base pairs and inhibition of DNA–topoisomerases I and II. Oxygen free radical formation from reduced doxorubicin intermediates is thought to be a mechanism associated with cardiotoxicity.
Epipodophyllotoxins Etoposide is a semisynthetic epipodophyllotoxin extracted from the root of Podophyllum peltatum (mandrake). It inhibits topoisomerase II activity by stabilizing the DNA–topoisomerase II complex; this process ultimately results in the inability to synthesize DNA, and the cell cycle is stopped in the G1 phase.
Vinca alkaloids The vinca alkaloids are derived from the periwinkle plant Vinca rosea. Upon entering the cell, vinca alkaloids bind rapidly to the tubulin. The binding occurs in the S phase at a site different from that associated with paclitaxel and colchicine. Thus, polymerization of microtubules is blocked, resulting in impaired mitotic spindle formation in the M phase.
Taxanes Paclitaxel and docetaxel (Taxotere) are semisynthetic derivatives of extracted precursors from the needles of yew plants. These drugs have a novel 14-member ring, the taxane. Unlike the vinca alkaloids, which cause microtubular disassembly, the taxanes promote microtubular assembly and stability, therefore blocking the cell cycle in mitosis. Docetaxel is more potent than paclitaxel in enhancing microtubular assembly and also induces apoptosis.
Camptothecin analogs include irinotecan and topotecan (Hycamtin). These semisynthetic analogs of the alkaloid camptothecin, derived from the Chinese ornamental tree Camptotheca acuminata, inhibit topoisomerase I and interrupt the elongation phase of DNA replication.
Monoclonal antibodies Although monoclonal antibodies (MAbs) have been used in cancer therapeutics since the late 1990s, the number of new agents in this class is growing exponentially. Several unconjugated MAbs have established utility in medical oncology as highly targeted therapies. The earliest therapeutic MAb to show convincing utility in medical oncology was rituximab (Rituxan), approved in 1997 for the treatment of non-Hodgkin lymphoma. This antibody targets the CD20 antigen found on B-cell lymphocytes and can be used clinically as a single agent or in association with combination chemotherapy. Another MAb, trastuzumab (Herceptin), has shown excellent activity in combination with chemotherapy in breast cancer patients whose tumor cells overexpress the human epidermal growth factor receptor 2 (HER2) protein. Finally, alemtuzumab (Campath) is a MAb that recognizes the CD52 antigen expressed on both B-cell and T-cell lymphocytes. This agent is useful in the treatment of chemotherapy-refractory B-cell chronic lymphocytic leukemia.
In 2004, two new MAbs were approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced colorectal cancer: bevacizumab (Avastin) and cetuximab (Erbitux). Bevacizumab binds to the vascular endothelial growth factor (VEGF) and prevents ligand-induced VEGF receptor activation, which blocks the stimulation of endothelial cell growth and inhibits new blood vessel formation in tumors that secrete VEGF. Cetuximab binds the EGFR on the surface of tumor cells, ultimately leading to down-regulation of this signaling pathway. This process blocks tumor growth and proliferation and can reverse tumor resistance to chemotherapeutic agents such as irinotecan. Cetuximab is now also indicated for head and neck cancer. Bevacizumab has received indications in lung and breast cancers.
Panitumumab (Vectibix), approved by the FDA in 2006, is another MAb that targets EGFR and is indicated for use in colorectal cancer that has metastasized following standard chemotherapy.
A recent randomized trial found that the addition of bevacizumab to irinotecan- and 5-FU–based chemotherapy in newly diagnosed patients with advanced colorectal cancer significantly improved the response rate (45% vs 35%; P = .0029), duration of response (10.4 vs 7.1 months; P = .0014), and median survival (20.3 vs 15.6 months; P = .0003) compared with placebo. Grade 3 hypertension (10.9% vs 2.3%) and GI perforations (1.5% vs 0%) were more common in the bevacizumab arm, but overall, the bevacizumab therapy was thought to be well tolerated. This was the first randomized clinical trial demonstrating a survival benefit for antiangiogenic therapy.
Small-molecule targeted therapies Molecularly targeted therapies are designed to selectively interact with specific molecular pathways within cells to achieve a rational antitumor effect. The classic rationally designed molecularly targeted agent is imatinib (Gleevec), which was identified in screening studies designed to detect inhibitors of the Bcr-Abl tyrosine kinase, present in virtually all cases of chronic myelogenous leukemia. Originally synthesized as an inhibitor of platelet-derived growth factor receptor (PDGFR), it is also a potent inhibitor of the c-kit tyrosine kinase. Imatinib binds to the ATP-binding site and inhibits the tyrosine kinase’s ability to phosphorylate its substrates.