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CHAPTER 22 overexpressed in those cells, including molecules involved in cell signaling

PHARMACOLOGY 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 altera-
AND TOXICITY OF tions in any one of the critical steps required for drug activity; these steps
include drug uptake and distribution through the bloodstream or across the
ANTINEOPLASTIC DRUGS 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; interac-
tion 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
Benjamin Izar, Dustin Dzube, James M. Cleary, Constantine S. agent from the body through the kidneys or through metabolic transforma-
Mitsiades, Paul G. Richardson, Jeffrey A. Barnes, and Bruce A. Chabner tion. The underlying mutability of tumors leads to the spontaneous generation
of cells with alterations in drug uptake, transformation, inactivation, and tar-
get binding. In the presence of the selective pressure of drug, resistant tumors
SUMMARY replace sensitive cells as the dominant tumor population. Combination che-
motherapy overcomes resistance that carries specificity for single agents, but
the expression of multidrug resistance genes, as well as loss of the apoptotic
The safe and effective use of anticancer drugs in the treatment of hematologic
malignancies requires an in-depth knowledge of the pharmacology of these response, can result in resistance even to combination drug therapy.
agents. In this field of medicine, the margin of safety is narrow and the poten- In addition to the molecular determinants of drug action, pharmacokinet-
tial for serious toxicity is real. At the same time, anticancer drugs cure many ics (the disposition of drugs in humans) plays a critical role in determining drug
hematologic malignancies and provide palliation for others. The discovery effectiveness and toxicity. Drug regimens are designed to achieve a maximally
and development of treatments for leukemia and lymphoma have provided effective concentration in plasma and tumor cells for an effective duration of
a paradigm for approaches to the improved treatment of the more common exposure. Because of the potential of these agents for toxicity, it is critical for
solid tumors. hematologists and oncologists to understand the pathways of drug clearance
The intelligent use of these drugs begins with an understanding of their and to adjust dose in the presence of compromised organ function. Drugs such
mechanism of action. Cytotoxic anticancer drugs inhibit the synthesis of as methotrexate, hydroxyurea, and the newer purine antagonists (fludarabine
DNA or directly attack its integrity through the formation of DNA adducts and cladribine) are eliminated primarily by renal excretion and should not be
or enzyme-mediated breaks. These DNA-directed actions are recognized by used in full doses in patients with renal dysfunction. Similarly, hepatic dys-
repair processes and by the checkpoints that monitor DNA integrity, includ- function with an elevated serum bilirubin concentration should alert clinicians
ing most prominently p53. If DNA damage cannot be repaired, and if the DNA to decrease doses of the taxanes, vinca alkaloids, and the anthracyclines. In
damage reaches thresholds for activating programmed cell death, then DNA addition, clinicians must be alert to the potential for drug interactions, par-
damage is translated into tumor regression. Attention has turned to the pos- ticularly the ability of drugs that induce or inhibit cytochrome metabolism to
sibility of identifying molecular targets unique to tumor cells, or dramatically alter patterns of drug elimination.

Acronyms and Abbreviations: ABVD, Adriamycin (doxorubicin), bleomycin, by concentration 50 percent; IDH, isocitrate dehydrogenase; IL, interleukin;
vinblastine, and dacarbazine; ADCC, antibody-dependent cellular cytotoxic- IMiD, immunomodulatory drug; IRF4, interferon regulatory factor 4; IRIS,
ity; αKG, α-ketoglutarate; ALL, acute lymphocytic leukemia; AML, acute mye- International Randomized Study of Interferon and STI571; JAK, Janus-type
logenous leukemia; APL, acute promyelocytic leukemia; ara-C, cytarabine; tyrosine kinase; JMJC, Jumonji-C domain; MDR, multidrug resistance; MDS,
ara-CTP, cytarabine triphosphate; ara-G, arabinosylguanine; ara-GTP, arabi- myelodysplastic syndrome; mesna, sodium 2-mercaptoethane sulfon-
nosylguanine triphosphate; ara-U, arabinosyluracil; ATRA, all-trans retinoic ate; MLL, mixed-lineage leukemia; MOPP, nitrogen mustard, vincristine
acid; BCNU, bischloroethylnitrosourea; BCRP, breast cancer resistance protein (Oncovin), procarbazine, and prednisone; 6-MP, 6-mercaptopurine; MPN,
transporter; BET, bromodomain and extraterminal; BTK, Bruton tyrosine myeloproliferative neoplasm; MRI, magnetic resonance imaging; MRP,
kinase; CHF, congestive heart failure; CLL, chronic lymphocytic leukemia; multidrug resistance-associated protein; MTD, maximum tolerated dose;
CML, chronic myelogenous leukemia; COMFORT, Controlled Myelofibrosis MUGA, multigated acquisition scan; NK, natural killer; OCT1, organic cat-
Study with Oral JAK Inhibitor Treatment; CrCl, creatinine clearance; CYP, ion transporter-1; PDGFR, platelet-derived growth factor receptor; PEG,
cytochrome P450; dCK, deoxycytidine kinase; dCTP, deoxycytidine triphos- monomethoxypolyethylene glycol; PMF, primary myelofibrosis; PRC2,
phate; DHFR, dihydrofolate reductase; DNMT, DNA methyltransferase; DTIC, polycomb repressive complex 2; PRPP, phosphoribosyl pyrophosphate; PV,
dimethyltriazenoimidazole carboxamide; EPO, erythropoietin; ET, essential polycythemia vera; RARα, retinoic acid receptor-α; REMS, risk evaluation
thrombocythemia; etoposide, VP-16; EZH2, enhancer of zest homologue and mitigation strategy; RNR, ribonucleotide reductase; SAMe, S-ade-
2; FBP, folate-binding protein; GM-CSF, granulocyte-macrophage colony- nosyl-L-methionine; S-phase, synthetic-phase; STAT, signal transducer
stimulating factor; HDAC, histone deacetylase; hENT, human equilibrative and activator of transcription; teniposide, VM-26; 6-TG, 6-thioguanine;
nucleoside transporter; 2HG, 2-hydroxyglutarate; Hgb, hemoglobin; HGPRT, TKI, tyrosine kinase inhibitor; Topo II, topoisomerase II; TPMT, 5-thiopu-
hypoxanthine guanine phosphoribosyltransferase; IC , inhibiting growth rine-methyltransferase; TPO, thrombopoietin.
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