Page 974 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 857

extended periods of time to induce fetal hemoglobin and reduce including Burkett, and CNS lymphomas for over 30 years. It is
sickle crisis in patients with sickle cell anemia (Chapter 42). incorporated into DNA during replication and inhibits polymerase-α,
is cell cycle specific, and penetrates the blood–brain barrier. In rapidly
Folic Acid Analogs (e.g., Methotrexate) replicating cells, it stalls polymerase function, leading to replication
Folic acid analogues block the formation of thymidine, resulting in fork collapse and strand breaks at the replication fork, signaling
accumulation of UMP, leading to high levels of UTP, which is apoptosis and differentiation.
incorporated into DNA and causes purine nucleotide pool imbal-
ance, slowing DNA synthesis. These agents bind thymidylate synthase Mechanisms of Resistance
and dihydrofolate reductase, and disrupt cell cycle progression and Although ara-C remains the backbone of therapy for aggressive
cell division. Methotrexate polyglutamation results in higher affinity hematologic malignancies, resistance has been observed that is both
binding to DHFR and improved inhibition. Aminopterin, the first specific to the drug and nonspecific. Specific resistance could be due
antifolate, was used by Sidney Farber (reported in 1948) and became to nucleotide transport down regulation, uncommon in dividing
one the first chemotherapeutic agents to be administered with success cells. Inside the cell, ara-C is phosphorylated by deoxycytidine kinase
to children with acute lymphocytic leukemia (ALL). Methotrexate is to the active 5′-triphosphate derivative ara-CTP, whereas catabolism
the agent currently used in hematologic diseases, while the family of of ara-C by cytidine deaminase (CDD) to the nontoxic metabolite
agents includes pemetrexed and trimetrexate. Inhibition of folate- arabinoside uridine is a major pathway of detoxification that can be
dependent methyl transfer enzymes disrupts purine synthesis path- overcome by high-dose therapy. Low penetration into the cerebrospi-
5
ways. Toxicity of methotrexate is reversed by N -formyl FH 4, or nal fluid is overcome by bolus administration of very high doses:
2
leucovorin, which serves as a direct folate coenzyme. Since it has no 1–2 g/m over 1 hour. Other resistance mechanisms appear nonspe-
tumor selectivity, normal tissues in active cell cycle are affected, cific and result in leukemia tolerance to cell cycle arrest and induction
including mucosa, bone marrow and hair follicles, resulting in of apoptosis, tolerance to DNA strand breaks, and rapid cell division
mucositis, pancytopenia and alopecia. Prolonged use is associated after therapy.
with pulmonary and liver fibrosis. High-dose therapy and excessive
periods of high blood levels result in interstitial nephritis, sometimes Clinical Use
requiring dialysis, Standard induction therapy for AML includes a 5–7-day continuous
2
2
The most common resistance is due to amplification of DHFR infusion of 100–200 mg/m or high-dose ara-C at doses of 1–3 g/m
expression by upregulation of translation and gene amplification, over 1 hour every 12 hours. Many modifications to these schedules
including the establishment of minichromosomes with the DHFR have improved tolerance without sacrificing efficacy. For CNS leuke-
gene. A second mechanism is decreased affinity of DHFR to metho- mia, a depo form of ara-C has been developed with improved toler-
trexate. A third mechanism is decreased thymidylate synthase, and ance and sustained cerebrospinal fluid levels (Chapter 60).
the fourth mechanism of resistance is impaired methotrexate poly- Subcutaneous administration has provided responses in older
glutamate formation. individuals with AML or MDS who do not respond well to more
While use has diminished in recent years, methotrexate remains intensive induction therapy.
part of the regimen for maintenance in children and adults with ALL
(Chapter 66). It is also used to depress T-lymphocyte proliferation 5-Azacytidine and Decitabine
after allogeneic stem cell transplantation to prevent acute graft-versus- These agents were initially developed as antimetabolites but are more
host disease (GVHD). High-dose methotrexate, with careful blood effective at low doses that inhibit the function of histone demethyl-
level monitoring to prevent acute renal toxicity and mucositis, and ation, and are described below.
leucovorin rescue, is effective in the management of CNS leukemias,
primary CNS lymphoma, and high proliferative fraction (myc posi- Gemcitabine
tive, bcl6 positive and high KI67) intermediate- and high-grade Developed as an agent for the treatment of pancreatic cancer, gem-
lymphomas, including Burkitt. citabine has gained therapeutic attention for use in patients with
Hodgkin lymphoma and NHL, particularly in the relapsed state.
Like other nucleotide analogues, gemcitabine is a prodrug that is
Nucleoside Analogues phosphorylated by deoxycytidine kinase to gemcitabine diphosphate
(FdCDP) and gemcitabine triphosphate (dFdCTP), which, when
The nucleoside analogs exhibit structural similarities to naturally incorporated into DNA, stalls the polymerase-α, which adds one
occurring nucleosides and are incorporated into either DNA or RNA more deoxynucleotide to the elongating strand. The polymerase
with lethal consequences. Alternatively, they block key enzymes in de replication complex then falls off the DNA, causing replication fork
novo purine or pyrimidine biosynthesis. There are two broad collapse and chain termination. In addition, FdCDP is a potent
categories: inhibitor of ribonucleoside reductase, causing depletion of deoxyri-
bonucleotide pools and further encouraging dFdCTP incorporation
1. Pyrimidine analogs (e.g., ara-C, 5-azacytidine, gemcitabine) while disrupting DNA synthesis.
2. Purine analogs (e.g., 6-thioguanine [6-TG], 6-mercaptopurine, Specific resistance is caused by upregulation of deoxycytidine
fludarabine, chlorodeoxyadenosine, deoxycoformycin, clofarabine, deaminase, which metabolizes gemcitabine to 2,2′-difluorodeoxyuri-
nelarabine) dine. Nonspecific resistance emerges due to upregulation of membrane
transporters, although their role in clinical resistance is less clear.
These categories are not mutually exclusive; for example, some Numerous studies have identified the utility of adding gemcitabine
nucleoside analogs (e.g., ara-C and 6-TG) also inhibit enzymes to cisplatin and other agents for the treatment of both relapsed
involved in DNA or deoxyribonucleotide biosynthesis. These agents Hodgkin lymphoma and NHL, and CTCLs. The combination of
are predominantly cycle-active agents and in most cases are phase oxaliplatinum or cisplatin and gemcitabine is effective and well toler-
specific, being primarily active against cells in S phase. Because the ated, and the majority of patients remain eligible for autologous stem
growth fraction of hematologic malignancies tends to be higher than cell collection and transplantation.
that of nonhematologic malignancies, nucleoside analogs are particu-
larly useful in the former disorders. In contrast to alkylating agents, Fludarabine
nucleoside analogs have limited carcinogenic and leukemogenic Fludarabine was introduced 25 years ago as an agent with potent
potential. The fluorinated pyrimidines (e.g., 5-FU) are generally not activity against lymphoid malignancies and remains an active agent
used in treating hematologic disorders and are not discussed further. in CLL and other low-grade lymphomas. It has since emerged as an
ara-C has been used in the treatment of acute leukemias— agent in combination that is effective in leukemias, and in induction
particularly acute nonlymphocytic leukemias, aggressive lymphomas therapy for nonmyeloablative conditioning prior to allogeneic stem