Page 1000 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 883

remarkably resistant to temozolomide regardless of AGT activity or activity or a mutant form of DHFR (in the case of methotrexate),
its inhibition by BG, confirming the importance of MMR in sensitiv- an altered DNA polymerase-α (in the case of ara-C), or increased
ity to methylating agents. Of interest, MMR mutant cells are also activity of ribonucleotide reductase (through overexpression of either
two- to threefold resistant to cisplatin, perhaps because the cisplatin subunit). Finally, cytokinetic factors represent a common theme in
DNA adduct is bound by the MMR complex, slowing its recogni- the case of most (but not all) antimetabolites, in that a reduction
tion and repair by the nucleotide repair pathway and increasing its in the S-phase fraction generally leads to reduced drug sensitivity.
cytotoxicity. Such MMR-deficient cells also exhibit microsatellite Note that these resistance mechanisms are agent specific and are
instability, a measure of genomic instability and the propensity to distinct from the more general modes of resistance (e.g., increased
develop further mutations during therapy, leading to subclones of expression of BCL2) associated with defects in the distal cell death
resistant cells. Loss of PMS2 has been identified in a family of child- pathway.
hood lymphomas. Microsatellite instability is seen in acute leukemias
and in T-cell leukemias, suggesting both that these malignancies
have lost MMR function and that they are more prone to drug Mechanisms of Resistance to Signaling Inhibitors
resistance and acquisition of additional mutations that give rise to
further drug resistance. Evidence of microsatellite instability and loss The introduction of signaling inhibitors to the therapeutic armamen-
of MMR is present in some leukemias but is much more common tarium represents a significant advance in the treatment of hemato-
in treatment-related leukemias, again providing a mechanism of drug logic malignancies. As discussed in the previous sections, these agents
resistance. can inhibit with relative selectivity cellular signaling pathways essen-
tial for the survival of neoplastic cells. However, development of
Base Excision Repair resistance has been observed in vitro and in clinical practice, and
Methylating agents such as procarbazine and temozolomide form appears to be the rule rather than an exception with these agents. The
3
7
6
large numbers of N -A and N -G adducts in addition to O -mG mechanisms of resistance related to drug influx/efflux also can affect
3
6
7
(with TMZ, the relative amounts are 72 N mG:8 O mG:5 N mA). sensitivity to targeted agents. In addition, several other mechanisms
7
Thus, under normal circumstances, cells process many more N mG have been described for signaling inhibitors, including genetic altera-
3
6
and N mA lesions than O mG lesions, even though the latter appear tions, changes in protein expression, and activation of alternative
3
much more cytotoxic except in MMR-defective cells. Repair of N -A pathways.
7
and N -G adducts through BER is efficient and normally leads to
cell survival rather than cell death. Adducts are recognized by the
methylpurine glycosylase with removal of the base, generating an Genetic Modifications Leading to Resistance to
abasic (or AP) site. The AP site is then cleaved by the class II hydro- Signaling Inhibitors
lytic endonuclease (or AP endonuclease) generating a single-strand
break with a 5′ PO 4 , which becomes the substrate for DNA Cancer cells treated with kinase inhibitors tend to acquire genetic
polymerase-β, and to a lesser extent, polymerases-δ and -γ, followed modifications that overcome the inhibitory effects of these agents.
21
by DNA ligase (reviewed by Sancar ). Other compounds induce Point mutations are the most common mechanism of resistance
nucleotide pool imbalance, leading to misincorporation of bases that to TK inhibitors. The development of resistance against a specific
become substrates for BER. These compounds include folate antago- inhibitor can be the result of a preexisting cancer cell subpopulation
nists such as methotrexate, 5-FU, and, to a lesser extent, nucleoside carrying the mutation; once exposure to the drug occurs and sensitive
analogs such as fludarabine. Misincorporation of uracil after 5-FU cells die, this cell population experiences selective advantage. On the
inhibition of thymidilate synthase also leads to BER. Compounds to other hand, cell line studies have been able to induce the emergence
disrupt BER, such as TRC102, are now being developed and may of resistance to specific signaling inhibitors, suggesting that the
lead to combination therapy for hematologic malignancies. An initial genomic instability experienced by neoplastic cells facilitates emer-
phase I trial with TRC102 has been completed with pemetrexed, and gence of new mutations that may affect drug sensitivity.
a second trial with temozolomide continues. A third trial using the Mutations that confer resistance to a kinase inhibitor commonly
combination of fludarabine and TRC102 in patients with CLL has affect the affinity of the drug for the kinase domain without affecting
found remarkable efficacy in the first cohorts after relapsing from its catalytic activity. Other mutations affect the conformation of the
fludarabine (unpublished). kinase, making it less available to the inhibitor, and others decrease
the affinity of the kinase for ATP, affecting the efficacy of ATP-
competitive inhibitors.
Drug Resistance to Antimetabolites Genetic amplifications are common in cancer cells. Many signal-
ing inhibitors target pathways that present amplification of one of its
Although overlap exists, antimetabolites can be classified into nucleo- components. Further increases in gene amplification can affect the
side analogs that are incorporated into RNA or DNA (or both) and drug–target balance in favor of the latter. Gene amplifications result-
agents that inhibit de novo purine and pyrimidine biosynthetic path- ing in increases in target may be overcome by increasing the inhibitor
ways. Mechanisms of resistance to these agents fall into several broad dose, as it is done in clinical practice with imatinib; however, this is
categories. For example, many antimetabolites are prodrugs in that limited by the higher potential for adverse events.
they must be converted intracellularly into active nucleotide forms to Genetic modifications that don’t involve the target can also result
exert their cytotoxic actions. Consequently, events that interfere with in resistance. This can occur when mutations or amplifications result
cellular accumulation of drug or nucleotide formation will reduce in increased activity or expression of signaling molecules located
activity. Examples include decreased transport of methotrexate or downstream or parallel to the point of inhibition. These “escape”
decreased nucleotide formation of ara-C and 6-TG by reductions in mechanisms may be taken into consideration when designing com-
activity of deoxycytidine kinase or hypoxanthine–guanine phosphori- bination strategies for treatment with multiple targeted agents.
bosyltransferase, respectively. Alternatively, enhanced drug catabolism
reduces cytotoxicity. Examples include the deamination of ara-C
(to inactive ara-U) by CDD or catabolism of 6-TG by thiopurine FUTURE DIRECTIONS
methyltransferase. A third mechanism of resistance stems from the
presence of increased intracellular levels of a competing metabolite The treatment of hematologic malignancies has seen significant
(e.g., dCTP in the case of ara-C, or hypoxanthine or guanine in the progress over the last decades. The continuing expansion of the thera-
case of 6-TG). Fourth, alterations in the level of activity of a target peutic armamentarium with the addition of target-based therapies
enzyme or the presence of a mutant form that is a poor target of presents clinicians and researchers with several challenges. The first
inhibition will also confer resistance. Examples include increased problem is one of choice; with several agents identified as effective for