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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 861

Clinical Activity expressed in the leukemic cells of most patients with CML. The
recognition that the constitutively active TK BCR-ABL played a
Cisplatin, carboplatin, and oxaliplatin are used in the treatment of central role in the pathogenesis of chronic myeloid leukemia led
refractory lymphomas in a variety of combinations, and as part of to the search for potential inhibitors. The introduction of the TK
high-dose and intensification therapy for lymphomas as definitive inhibitor imatinib for treatment of CML is a major milestone in
treatment including prior to autologous stem cell transplantation. the development of targeted therapy for hematologic and neoplastic
disorders. The role of the BCR-ABL kinase in the pathogenesis of
CML and ALL and the use of BRC/ABL inhibitors in the treatment
Miscellaneous Agents of these disorders are discussed in further detail in Chapter 67.
Imatinib mesylate is the founding agent in the class of TK inhibi-
Among the agents included in this category, only plicamycin, bleo- tors. It causes direct inhibition of the BCR-ABL kinase, but is not
mycin, procarbazine, L-asparaginase, gallium nitrate, and glucocorti- absolutely specific for this molecule, as it also inhibits other kinases,
coids are of current interest to hematologists; these are discussed in including KIT (formerly designated c-KIT), platelet-derived growth
Appendix 57.6. factor (PDGF), stem cell factor (SCF), and TEL-ARG.
Radiographic crystallography studies show that imatinib mesylate
PHARMACOLOGY OF TARGETED competitively binds to the ATP-binding site of the ABL kinase and
stabilizes it in an inactive conformation. The 50% inhibitory concen-
ANTINEOPLASTIC AGENTS tration (IC 50) of imatinib mesylate for BCR-ABL is in the submicro-
molar range, and is substantially lower than the supramicromolar
Since the year 2000, the therapeutic arsenal available for treatment levels achievable in the plasma of patients receiving the drug by the
of hematologic malignancies has expanded to include a group of oral route.
drugs that have collectively been termed as “targeted agents.” Tradi- Despite the success with imatinib mesylate in the treatment of
tional chemotherapeutic drugs affect specific targets, many times chronic-phase CML and, to a lesser extent, accelerated or blast-phase
identified after the cytotoxic and clinical activity of these agents have CML, the preexistence or development of resistance represents a
been demonstrated. Dobbelstein and Moll describe three “waves” or major therapeutic challenge that can occur at any stage of the disease.
4
“epochs” in anticancer drug development. The first wave includes Primary or secondary resistance can develop through a variety of
traditional chemotherapeutic agents, comprised mostly of drugs that mechanisms. BCR-ABL–dependent mechanisms correspond to the
affect DNA replication, repair and cell division; these drugs are emergence of mutations in ABL kinase domain, which can be located
nonspecific and can affect normal cells, but take advantage of the in the imatinib binding site, the P loop, the catalytic domain, or the
increased proliferation of cancer cells to exert their cytotoxic activity. activation loop. Many of these mutations are present at the time of
Second-wave drugs target cellular signals, including those mediated diagnosis and resistant clones emerge after exposure to imatinib.
by surface receptors and protein kinases. Monoclonal antibodies are Resistance mechanisms independent of BCR-ABL include develop-
included in this second wave. The targets of signaling inhibitors are ment of multidrug resistance mechanisms (e.g., PGP related);
diverse, and include the products of oncogenes, essential for the decreased levels of human organic cation transporter; acquisition of
development and survival of neoplasms (“oncogene addition”). The additional genetic abnormalities (clonal evolution) including acquisi-
prototype of this class of agents is imatinib, targeting the chimeric tion of an additional Philadelphia-positive chromosome (Ph+),
product of B-cell receptor (BCR)-ABL in CML. Other cellular signal- trisomy 8 and isochromosome 17q, increased expression of the
ing proteins are not the product of oncogenes, but have an essential BCR-ABL protein, and SRC kinase overexpression.
role in intracellular processes of malignant cells. This state is known Imatinib also has activity in diseases dependent on other kinases,
as “nononcogene addiction” and has expanded the number of targets such as PDGF receptor (PDGFR)α, PDGFRβ, or KIT, and is active
that can be used for cancer treatment with signaling inhibitors. against myeloproliferative disorders associated with eosinophilia and
Examples of the latter agent class include inhibitors of mammalian FIP1L1/PDGFRα or PDGFRβ fusion genes, as well as against sys-
target of rapamycin (mTOR) and BTK. The third wave of anticancer temic mastocytosis without KIT D816V mutation (Chapters 71 and 72).
drugs target cellular mechanisms and effector systems distinct from Common adverse events due to imatinib include fluid overload
those targeted by drugs of the first two waves, but that are still and edema, and development of heart failure, fatigue, rash, and
essential for the survival of cancer cells. The cellular processes targeted myelosuppression. Gastrointestinal side effects are common, and
by drugs of the third wave are those that contain several types of nausea and vomiting are frequent reasons for poor compliance.
constitutive stress experienced by cancer cells (separate from replica-
tive stress), including proteotoxic stress leading to abnormal protein Dasatinib
folding and increased protein degradation (targeted by heat-shock Dasatinib is a second-generation ABL kinase inhibitor approved for
protein inhibitors and proteasome inhibitors), DNA damage (tar- the treatment of CML. Dasatinib is an oral multikinase inhibitor,
geted by PARP inhibitors), DNA modifications (targeted by hypo- affecting BCR-ABL, KIT, PDGFR and src kinases. It binds the ATP
methylating agents and HDACs), prosurvival balance in organelles binding site of ABL in an opposite direction to imatinib, can inhibit
governing cell survival (targeted by BCL2 inhibitors), increased need active and inactive forms of the kinase, and requires fewer points of
for protein transport (inhibited by nuclear transport inhibitors), as contact. This reduced structural stringency in kinase inhibition allows
well as transcriptional, ribosomal, metabolic, and oxidative stress, for inhibition of all kinase mutations, with the exception of the
targeted by several other drugs in development. Other agents not T315I mutation.
easily included in these three waves include immunomodulatory Compared with imatinib, dasatinib is several hundred times more
drugs (thalidomide, lenalidomide, and pomalidomide), as well as potent as an inhibitor of ABL. Initial studies demonstrated dasatinib-
agents promoting cancer cell differentiation (all-trans retinoic acid). induced responses in patients who had developed resistance to ima-
tinib treated in the chronic, accelerated, and blast phase of CML.
Signaling Inhibitors (Table 57.4) There is a high response rate in patients with wild-type sequences
of bcr-abl and also in patients with mutations in the ABL protein
Imatinib Mesylate and Other BCR-ABL conferring resistance to imatinib, with the exception of the T316I
mutation.
Kinase Inhibitors As a multikinase inhibitor, dasatinib has a broader and alternative
toxicity profile, with pulmonary edema, pleural effusions, and throm-
Imatinib Mesylate bocytopenia being the more frequent adverse effects. Recently, higher
Imatinib mesylate is a phenylaminopyrimidine developed as an rates of pulmonary hypertension have been observed in patients
inhibitor of the constitutively active tyrosine kinase (TK) BCR-ABL, receiving dasatinib.