Page 966 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 57

PHARMACOLOGY AND MOLECULAR MECHANISMS OF

ANTINEOPLASTIC AGENTS FOR HEMATOLOGIC MALIGNANCIES

Stanton L. Gerson, Paolo F. Caimi, Basem M. William, and Richard J. Creger

The treatment of patients with hematologic malignancies has been AKT activation; disruption of replication sequences; loss of DNA
revolutionized over the past decades as new therapeutic targets con- repair enzymes such as mismatch repair (MMR) enzymes; loss of
tinue to be identified through cellular and molecular studies of these proper homologous recombination from a defect in the BRCA–
conditions. These investigations have spawned the discovery, clinical Fanconi pathways; and loss of ATM/ATR kinases, which can give rise
evaluation, and US Food and Drug Administration (FDA) approval to chromosomal recombination, loss, and microsatellite instability,
of new mechanistic-based therapeutic agents. A surprising number of and loss of checkpoint regulation. These events can give rise to
these agents have progressed from the discovery phases to validation, intraclonal emergent point mutations, translocations, and intragenic
animal modeling, and successful clinical testing. The results have led losses that might not only result in malignant transformation, but
to a virtual explosion in the therapeutic armamentarium and an also lead to disruption of genomic stability and selection in favor of
increase in the spectrum of drugs including small molecules, mono- proliferative and apoptosis-resistant subclones. Leukemic clonal
clonal antibodies, radiolabeled antibodies, drug immunoconjugates, evolution favors drug resistance.
immunotoxins, and complex delivery systems. This chapter provides Common mechanisms may be involved in events associated with
information on new and existing therapeutic agents available for the malignant transformation and the development of mutations that
treatment of patients with hematologic malignancies. The chapter result in tumor heterogeneity. For example, the cell cycle checkpoint
reviews the “classic” agents as well as the newly developed, target- and tumor suppressor gene, TP53, is induced during DNA damage,
based agents. Both cytotoxic and growth-inhibitory agents are leading to G 1 arrest and, if the damage is too severe to repair, cell
covered; however, the use of therapeutic antibodies and antibody death by apoptosis occurs. The presumed goal of this process is to
conjugates is reviewed within the chapters dealing with specific eliminate cells that develop deleterious mutations as a result of
diseases. damage to the genome. Loss of TP53 may not only increase cellular
survival by inhibiting the cell death process, but may also promote
TUMOR CELL HETEROGENEITY OF HEMATOLOGIC the transmission of mutations that would otherwise be deleted. In
this manner, a defect of the cell death pathway can have multiple
MALIGNANCIES consequences, including (1) selection of cells exhibiting a growth
advantage over their normal counterparts, (2) development of drug
Whereas hematologic malignancies are of clonal origin (i.e., they are resistance, and (3) promotion of mutations that result in either (1)
derived from a single transformed cell), individual neoplastic cells or (2), as well as neoplastic cell heterogeneity. Age-dependent changes
from a patient’s malignancy exhibit a great deal of phenotypic diver- in these processes may explain the more favorable behavior of leuke-
sity and acquire secondary mutations that affect proliferation, drug mias and lymphomas in response to chemotherapy in young patients
sensitivity, and resistance. This diversity likely arises from the progeny than older patients.
of clonal populations and subsets of stem cells. In animal models, it A model of the relationship between tumor growth rate, the
has been shown that the clones themselves can give rise to progeny occurrence of spontaneous mutations, and the development of drug
that can transmit the clonal malignancy after transplantation into resistance was first described by Goldie and Coldman and is referred
secondary recipients, suggesting that stem cells are not required to to as the Goldie and Coldman hypothesis. In this model, the size of
transmit the malignant phenotype. a tumor depends on a complex interaction between tumor growth
New evidence indicates that leukemia stem cells are more quies- rate and cell loss, the latter stemming from the status of the cell
cent, have higher levels of protective proteins such as efflux pumps death process, exhaustion of available nutrients, and outstripping
for drugs, and have higher levels of DNA repair proteins or antiapop- of the blood supply. As tumors increase in size, the cell death rate
totic proteins than the more abundant cell making up the circulating tends to increase. The heterogeneous nature of additional muta-
population of cells. Tumor cell heterogeneity arises as a consequence tions makes it likely that multiple mechanisms of resistance will
of spontaneous mutational events, changes in gene promoter meth- develop as well. From an operational standpoint, this model has
ylation, abnormal expression of transcription factors, lymphoid clear implications for the rational design of therapeutic strategies and
reactivity, and cytokine responsiveness. For example, a mutation or provides a basis for early and intensive combination drug therapy.
change in expression that renders a hematopoietic cell clone autono- The successful implementation of this strategy is exemplified by
mous or growth factor–independent would be expected to render the administration of dose-intensive multidrug regimens (i.e., the
such cells less susceptible to adverse environmental conditions (e.g., BEACOPP [bleomycin, etoposide, Adriamycin, cyclophosphamide,
growth factor withdrawal). Similarly, one would also predict that a vincristine (Oncovin) procarbazine, and prednisone] regimen
genetic change facilitating cell cycle entry or disruption of cellular in Hodgkin lymphoma, CODOX-M-IVAC [cyclophoshamide,
maturation would ultimately lead to overgrowth of affected clones. vincristine, doxorubicin, high-dose methotrexate alternating with
For obvious reasons, mutations that interfere with drug metabolism ifosfamide, etoposide and high-dose cytarabine] in Burkitt lym-
or the cell death pathway itself would provide a net survival advan- phoma [non-Hodgkin lymphoma (NHL)]) and combinations of
tage, particularly under the selection pressure of cytotoxic drug cytotoxic agents with monoclonal antibodies, such as CHOP (cyclo-
treatment. phosphamide, hydroxydaunorubicin, vincristine [Oncovin], and
Malignant myeloid and lymphoid cells have many reasons to have prednisone)–rituximab, which are potentially curative when given
increased mutational rates. Genomic instability can arise from dys- early in the course of the disease. Other examples include combined
regulation of the cell cycle machinery because of a number of events, use of multitargeted agents such as lenalidomide and bortezomib for
including perturbations of cyclins leading to MYC overexpression; myeloma, fludarabine, cyclophosphamide and rituximab for chronic

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