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

1706 throughout the cytoplasm (exploded mitosis) or may clump in
unusual groupings, such as balls or stars. Cells blocked in mitosis
undergo changes characteristic of apoptosis.
In addition to their key role in the formation of mitotic spindles,
microtubules are found in high concentration in the brain and
contribute to other cellular functions such as movement, phagocytosis,
and axonal transport. Side effects of the vinca alkaloids, such as
their neurotoxicity, may relate to disruption of these functions.
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Drug Resistance. Despite their structural similarity, the vinca alkaloids
have unique individual patterns of clinical effectiveness (see
the individual vinca alkaloid sections). However, in most experimental
systems, they share cross-resistance. Their antitumor effects
are blocked by multidrug resistance mediated by the mdr gene and
its glycoprotein. Tumor cells become cross-resistant to a wide range
of chemically dissimilar agents (the vinca alkaloids, epipodophyllotoxins,
anthracyclines, and taxanes). Chromosomal abnormalities
consistent with gene amplification have been observed in resistant
cells in culture, and the cells contain markedly increased levels of
the P-glycoprotein, a membrane efflux transporter (Endicott and
Ling, 1989). Ca 2+ channel blockers such as verapamil can reverse
resistance of this type in vitro; however, clinical trials of resistancereversing
agents have been disappointing. Other membrane transporters,
such as the MRP and the closely related breast cancer
resistance protein, may mediate multidrug resistance. Still other
forms of resistance to vinca alkaloids stem from mutations in β
tubulin or in the relative expression of isoforms of β tubulin; both
changes prevent the inhibitors from effectively binding to their target.
Cytotoxic Actions. The very limited myelosuppressive action of vincristine
makes it a valuable component of several combination therapy
regimens for leukemia and lymphoma, while the lack of severe
neurotoxicity of vinblastine is a decided advantage in lymphomas
and in combination with cisplatin against testicular cancer.
Vinorelbine, which causes a mild neurotoxicity as well as myelosuppression,
has an intermediate toxicity profile. Vincristine is a
standard component of regimens for treating pediatric leukemias,
lymphomas, and solid tumors, such as Wilms tumor, neuroblastoma,
and rhabdomyosarcoma. In large-cell non-Hodgkin’s lymphomas,
vincristine remains an important agent, particularly when used in
the CHOP regimen with cyclophosphamide, doxorubicin, and prednisone.
Vinblastine is employed in treating bladder cancer, testicular
carcinomas, and Hodgkin’s disease. Vinorelbine has activity
against non–small cell lung cancer and breast cancer.
Absorption, Fate, and Excretion. The liver cytochromes extensively
metabolize all three agents, and the metabolites are excreted in the
bile (Robieux et al., 1996). Only a small fraction of a dose (<15%) is
found in the urine unchanged. In patients with hepatic dysfunction
(bilirubin >3 mg/dL), a 50-75% reduction in dose of any of the vinca
alkaloids is advisable, although firm guidelines for dose adjustment
have not been established. The pharmacokinetics of each of the three
drugs are similar, with an elimination t 1/2
of 20 hours for vincristine,
23 hours for vinblastine, and 24 hours for vinorelbine.
Vinblastine
Therapeutic Uses. Vinblastine sulfate (VELBAN, others) is given
intravenously; special precautions must be taken against subcutaneous
extravasation, because this may cause painful irritation and ulceration.
The drug should not be injected into an extremity with impaired
circulation. After a single dose of 0.3 mg/kg of body weight, myelosuppression
reaches its maximum in 7-10 days. If a moderate level
of leukopenia (~3000 cells/mm 3 ) is not attained, the weekly dose
may be increased gradually by increments of 0.05 mg/kg of body
weight. In regimens designed to cure testicular cancer, vinblastine is
used in doses of 0.3 mg/kg every 3 weeks. Doses should be reduced
by 50% for patients with plasma bilirubin >1.5 mg/dL.
One important clinical use of vinblastine is with bleomycin
and cisplatin (see “Therapeutic Uses” under “Bleomycin”) in the
curative therapy of metastatic testicular tumors, although it has been
supplanted by etoposide or ifosfamide in this disease. It is a component
of the standard curative regimen for Hodgkin’s disease [doxorubicin
(ADRIAMYCIN), bleomycin, vinblastine, and dacarbazine
(ABVD)]. It also is active in Kaposi sarcoma, neuroblastoma,
Langerhans cell histiocytosis, carcinoma of the breast, and choriocarcinoma.
Clinical Toxicities. The nadir of the leukopenia that follows the
administration of vinblastine usually occurs within 7-10 days, after
which recovery ensues within 7 days. Other toxic effects of vinblastine
include mild neurological manifestations. GI disturbances
including nausea, vomiting, anorexia, and diarrhea may be encountered.
The syndrome of inappropriate secretion of antidiuretic hormone
has been reported. Loss of hair, stomatitis, and dermatitis
occur infrequently. Extravasation during injection may lead to cellulitis
and phlebitis.
Vincristine
Therapeutic Uses. Vincristine sulfate (VINCASAR PFS,
others) used together with glucocorticoids is the treatment
of choice to induce remissions in childhood
leukemia and in combination with alkylating agents
and anthracycline for pediatric sarcomas; the common
intravenous dosage for vincristine is 2 mg/m 2 of body
surface area at weekly or longer intervals. Vincristine
seems to be tolerated better by children than by adults,
who may experience severe, progressive neurological
toxicity and require a lower dose of 1.4 mg/m 2 .
Administration of the drug more frequently than every
7 days or at higher doses increases the toxic manifestations
without proportional improvement in the
response rate. Precautions also should be used to avoid
extravasation during intravenous administration of vincristine.
Doses should be reduced by 50% or 75% for
patients with plasma bilirubin >1.5 mg/dL or >3 mg/dL,
respectively.
Clinical Toxicities. The clinical toxicity of vincristine is
mostly neurological. Early sensory changes do not warrant
dose reduction. The more severe neurological manifestations
may be avoided or reversed by either
suspending therapy or reducing the dosage upon first
evidence of motor dysfunction. Severe constipation,