DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Deoxyadenosine also inactivates S-adenosyl homocysteine hydrolase.
The resulting accumulation of S-adenosyl homocysteine is particularly
toxic to lymphocytes. Pentostatin also can inhibit RNA
synthesis, and its triphosphate derivative is incorporated into DNA,
resulting in strand breakage. Although the precise mechanism of
cytotoxicity is not known, it is probable that the imbalance in purine
nucleotide pools accounts for its antineoplastic effect in hairy cell
leukemia and T-cell lymphomas.
Absorption, Fate, and Excretion. Pentostatin is administered intravenously,
and a single dose of 4 mg/m 2 has a mean terminal t 1/2
of
5.7 hours. The drug is eliminated almost entirely by renal excretion.
Proportional reduction of dosage is recommended in patients with
renal impairment as measured by reduced CrCl.
Therapeutic Uses. The recommended dose is 4 mg/m 2 administered
every other week intravenously. After hydration with 500-1000 mL
of 5% dextrose in half-normal (0.45%) saline, the drug is administered
by rapid intravenous injection or by infusion over a period of
≤30 minutes, followed by an additional 500 mL of fluids.
Pentostatin is extremely effective in producing complete remissions
(58%) and partial responses (28%) in hairy cell leukemia (Grever
et al., 2003). It largely has been superseded by cladribine.
Clinical Toxicities. Toxic manifestations include myelosuppression,
GI symptoms, skin rashes, and abnormal liver function studies.
Depletion of normal T cells occurs, and neutropenic fever and opportunistic
infections may result. Immunosuppression may persist for
several years after discontinuation of pentostatin therapy. At high
doses (10 mg/m 2 ), major renal and neurological complications are
encountered. Pentostatin in combination with fludarabine phosphate
may result in severe or even fatal pulmonary toxicity.
of myrtle, have been described in medicinal folklore. Periwinkle
extracts attracted interest because of their hypoglycemic effects in
diabetes. Purified alkaloids, including vinblastine and vincristine,
caused regression of an acute lymphocytic leukemia in mice and
were among the earliest clinical agents for treatment of leukemias,
lymphomas, and testicular cancer. A closely related derivative,
vinorelbine, has important activity against lung and breast cancer.
Chemistry. The vinca alkaloids are asymmetrical dimeric compounds
formed by condensation of the vindoline and catharanthine
subunits.
1705
CHAPTER 61
CYTOTOXIC AGENTS
III. Natural Products
MICROTUBULE-DAMAGING AGENTS
Several anticancer agents act through the microtubules,
either causing disorganized stabilization of microtubules
in areas away from the centriole or causing
destabilization of the mitotic spindle, interfering with
mitosis. The vinca alkaloids are effective in the treatment
of hematological malignancies, breast, germ cell,
and lung cancers, whereas the taxanes have become
leading agents in the treatment of ovarian, breast, head
and neck, and lung cancers. A new class of agents, the
epothilones, resembles the taxanes in their action but
has limited cross-resistance with taxanes; the only
approved epothilone in the U.S., ixabepilone, is indicated
for metastatic breast cancer.
VINCA ALKALOIDS
History. The beneficial properties of the Madagascar periwinkle
plant, Catharanthus roseus (formerly called Vinca rosea), a species
Structure A
Structure B
Mechanism of Action. The vinca alkaloids are cellcycle–specific
agents and, in common with other drugs
such as colchicine, podophyllotoxin, the taxanes, and
the epothilones, block cells in mitosis. The biological
activities of the vincas can be explained by their ability
to bind specifically to β tubulin and to block its polymerization
with α tubulin into microtubules.
When cells are incubated with vinblastine, the microtubules
dissolve and highly regular crystals form, containing 1 mole of
bound vinblastine per mole of tubulin. Cell division arrests in
metaphase. In the absence of an intact mitotic spindle, duplicated
chromosomes cannot align along the division plate. They disperse