The discovery and development of curative treatments for hemologic malignancies have created a paradigm for effective combination therapy now adopted in treating common solid tumors. 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 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. In the past 2 decades, 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 as for cytotoxic drugs. The underlying mutability of tumors leads to the selection of tumor cell with mutations that affect drug uptake, activation or inactivation, and target binding. These resistant tumors emerge as the dominant tumor population. Combination chemotherapy overcomes resistance to single agents, but multidrug resistance mechanisms, such as amplification of the multidrug resistant transporter, or loss of the apoptotic response, can result in broad-based resistance.
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 interindividual variability in pharmacokinetics, and 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 hepatic or renal function. In addition, clinicians must be alert to the potential for drug interactions, particularly the ability of drugs that induce or inhibit cytochrome P450 metabolism to alter patterns of drug elimination. Pharmacokinetic monitoring has a standard role in the use of certain therapies, particularly high-dose methotrexate, and in the evaluation of new drugs or new drug combinations.
Inherited genetic variations in drug-metabolizing enzymes may lead to an increased risk of drug toxicity and may alter the antitumor response. The most important of these familial syndromes affecting treatment of leukemia is the deficiency of thiopurine methyltransferase, which slows the elimination of 6-mercaptopurine and leads to unanticipated toxicity during maintenance chemotherapy for acute lymphocytic leukemia. To ensure appropriate dosing, and management of toxicity, there ...