Antineoplastic Agents

Few categories of medication have a narrower therapeutic index and a greater potential for causing harmful side effects than do the antineoplastic drugs. A thorough understanding of their pharmacology, drug interactions, and clinical pharmacokinetics is essential for safe and effective use. The diversity of agents used to treat neoplastic disease is summarized in Table 51-1. Figure 51-1 shows some of the common targets for chemotherapeutic agents currently used to treat neoplastic disease.

In designing specific regimens for clinical use, many factors must be considered. Drugs are most effective in combination, and may be synergistic because of their biochemical interactions. It is more effective to combine drugs that do not share common mechanisms of resistance and do not overlap in their major toxicities. Cytotoxic drugs should be used as close as possible to their maximum individual doses and should be given as frequently as possible to discourage tumor regrowth and to maximize dose intensity—the dose given per unit time—a key parameter in the success of chemotherapy. Since the tumor cell population in patients with clinically detectable disease exceeds 109 cells, and since each cycle of therapy kills <99% of the cells, it is necessary to repeat treatments in multiple cycles to eradicate tumor cells.

the cell cycle An understanding of cell-cycle kinetics is essential for the proper use of antineoplastic agents (Figure 51-2). Many of the most effective cytotoxic agents damage DNA, and their toxicity is greater during the S, or DNA synthetic, phase of the cell cycle. Others, such as the vinca alkaloids and taxanes, block formation of a functional mitotic spindle in M phase. Human neoplasms that are most susceptible to chemotherapy are those with a high percentage of cells undergoing division. Similarly, normal tissues that proliferate rapidly (e.g., bone marrow, hair follicles, and intestinal epithelium) are most subject to damage by cytotoxic drugs, which often limits their usefulness. Conversely, slowly growing tumors with a small growth fraction (e.g., carcinomas of the colon or non-small cell lung cancer) often are less responsive to cycle-specific drugs. Understanding of cell-cycle kinetics and the controls of normal and malignant cell growth is crucial to the design of current therapeutic regimens and the search for new drugs.

achieving therapeutic balance and efficacy The treatment of most cancer patients requires a skillful interdigitation of multiple treatment modalities, including surgery and irradiation, with drugs. Each of these forms of treatment carries its own risks and benefits. Not all drug regimens are appropriate for all patients, and factors such as renal and hepatic function, bone marrow reserve, general performance status, and concurrent medical problems must be considered. Beyond those considerations, however, are less quantifiable factors such as the likely natural history of the tumor being treated, the patient's willingness to undergo difficult and potentially dangerous treatments, the patient's physical and emotional tolerance for side effects, and the likely long-term gains and risks involved.

One of the greatest challenges of therapeutics is to adjust dose to achieve a therapeutic, but nontoxic, outcome. While it is customary to base dose on body surface area for individual patients, dose adjustment based on renal function or on pharmacokinetic monitoring can meet specific targets such as desired drug concentration in plasma or area under the concentration-time curve (AUC), a measure of tissue exposure. For example, thrombocytopenia caused by carboplatin is a direct function of AUC, which in turn is determined by renal clearance of the parent drug. Basic pharmacoki-netic principles can be thus used to achieve a desired AUC for carboplatin based on creatinine clearance. Similarly, therapeutic success during high-dose therapy for pediatric acute lymphoblas-tic leukemia (ALL) is related to achieving targeted methotrexate concentrations in plasma. Monitoring of steady-state levels of methotrexate allows dose adjustment and improves outcome.

Molecular tests increasingly are used to identify patients likely to benefit from treatment and those at highest risk of toxicity. Pretreatment testing to select patients for response to treatment is standard practice for hormonal therapy of breast cancer and for treatment with antibodies such as

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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