The safe and effective use of anticancer drugs in the treatment of hematologic malignancies requires an in-depth knowledge of the pharmacology of these agents. In this field of medicine, the margin of safety is narrow and the potential for serious toxicity is real. At the same time, anticancer drugs cure many hematologic malignancies and provide palliation for others. The discovery and development of treatments for leukemia and lymphoma have provided a paradigm for approaches to the improved treatment of the more common solid tumors.
The intelligent use of these drugs begins with an understanding of their mechanism of action. Cytotoxic anticancer drugs inhibit the synthesis of DNA or directly attack its integrity through the formation of DNA adducts or enzyme-mediated breaks. These DNA-directed actions are recognized by repair processes and by the checkpoints that monitor DNA integrity, including most prominently p53. If DNA damage cannot be repaired, and if the DNA damage reaches thresholds for activating programmed cell death, then DNA damage is translated into tumor regression. Attention has turned to the possibility of identifying molecular targets unique to tumor cells, or dramatically overexpressed in those cells, including molecules involved in cell signaling and cell-cycle control, but the principles of drug action and resistance to these compounds remain the same. Resistance to drug action can arise from alterations in any one of the critical steps required for drug activity; these steps include drug uptake and distribution through the bloodstream or across the blood–brain barrier; transport across the cell membrane; transformation of the parent drug to its active form within the tumor cell or in the liver; interaction of the drug with its target protein or nucleic acid; enzymatic or chemical inactivation of the agent; drug transport out of the cell; and elimination of the agent from the body through the kidneys or through metabolic transformation. The underlying mutability of tumors leads to the spontaneous generation of cells with alterations in drug uptake, transformation, inactivation, and target binding. In the presence of the selective pressure of drug, resistant tumors replace sensitive cells as the dominant tumor population. Combination chemotherapy overcomes resistance that carries specificity for single agents, but the expression of multidrug resistance genes, as well as loss of the apoptotic response, can result in resistance even to combination drug therapy.
In addition to the molecular determinants of drug action, pharmacokinetics (the disposition of drugs in humans) plays a critical role in determining drug effectiveness and toxicity. Drug regimens are designed to achieve a maximally effective concentration in plasma and tumor cells for an effective duration of exposure. Because of the potential of these agents for toxicity, it is critical for hematologists and oncologists to understand the pathways of drug clearance and to adjust dose in the presence of compromised organ function. Drugs such as methotrexate, hydroxyurea, and the newer purine antagonists (fludarabine and cladribine) are eliminated primarily by renal excretion and should not be used in full doses in patients with ...
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