PLANT-DERIVED
PRODUCTS
Three classes of
plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine),
the epipodo-phyllotoxins (etoposide and teniposide), and the tax-anes
(paclitaxel and taxotere), are used in cancer chemotherapy. These classes
differ in their structures and mechanisms of action but share the multidrug
re-sistance mechanism, since they are all substrates for the multidrug
transporter P-glycoprotein.
Vincristine (Oncovin) and vinblastine (Velban) are both produced by the leaves
of the periwinkle plant. Despite their structural similarity, there are
significant differences between them in regard to clinical usefulness and
toxicity.
The vinca alkaloids bind avidly to tubulin, a class of
proteins that form the mitotic spindle during cell divi-sion. The drugs cause
cellular arrest in metaphase dur-ing mitosis, and cell division cannot be
completed. Although the vinca alkaloids usually have been re-garded as phase
specific in the cell cycle, some mam-malian cells are most vulnerable in the
late S-phase.
Resistance to vinca alkaloids has been correlated with a decreased rate of drug uptake or an increased drug efflux
from these tumor cells. Cross-resistance usu-ally occurs with anthracyclines,
dactinomycin, and podophyllotoxins.
Both vincristine and
vinblastine are extensively bound to tissues, and only small amounts of the
drug are distributed to the brain or CSF. The plasma disappear-ance of
vinblastine and vinorelbine is triphasic. Similar clinical pharmacokinetics
have been noted with vin-cristine and vinorelbine. Biliary excretion is the
major route of drug excretion.
Vincristine is an important
component of the cura-tive combination chemotherapy for acute lymphoblas-tic
leukemia, Hodgkin’s disease (the MOPP regimen), and non-Hodgkin’s lymphomas. It
is also used in several regimens for pediatric solid tumors, including Wilms’
tu-mor, Ewing’s sarcoma, rhabdomyosarcoma, and neu-roblastoma; in adult tumors
of the breast, lung, and cervix; and in sarcomas. Its relative lack of
myelosup-pression makes it more attractive than vinblastine for use in
combination with myelotoxic drugs. Vinblastine is especially useful in
testicular carcinomas and is also ac-tive in Hodgkin’s disease, other types of
lymphomas, breast cancer, and renal cell carcinoma.
Vinorelbine is particularly
useful in the treatment of advanced non–small cell lung cancer and can be
admin-istered alone or in combination with cisplatin. It is thought to
interfere with mitosis in dividing cells through a relatively specific action
on mitotic microtubules.
Neurological toxicity is the
major dose-limiting tox-icity of vincristine, whereas bone marrow toxicity is
lim-iting for vinblastine. Severe neutropenia occurs in ap-proximately half of
the patients receiving vinorelbine. Severe leukopenia is the major side effect
of vinblas-tine. These drugs are potent local blistering agents and will
produce tissue necrosis if extravasated.
Etoposide (VePesid) is a semisynthetic derivative
of podophyllotoxin that is produced in the roots of the American mandrake, or
May apple. Unlike podophyllo-toxin and vinca alkaloids, etoposide does not bind
to mi-crotubules. It forms a complex with the enzyme topoiso-merase II, which
results in a single-strand breakage of DNA. It is most lethal to cells in the
S- and G2-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased
cellular drug accumulation.
Etoposide is most useful
against testicular and ovar-ian germ cell cancers, lymphomas, small cell lung
can-cers, and acute myelogenous and lymphoblastic leukemia. Toxicities include
mild nausea, alopecia, aller-gic reaction, phlebitis at the injection site, and
bone marrow toxicity.
Teniposide (VM-26, Vumon) is closely related to etopo-side
in structure, mechanisms of action and resistance, and adverse effects. It is
more lipophilic and approxi-mately threefold more potent than etoposide. Its
major uses have been in pediatric cancers, particularly in acute lymphoblastic
leukemias.
Paclitaxel (Taxol) is a highly complex, organic
com-pound isolated from the bark of the Pacific yew tree. It binds to tubulin
dimers and microtubulin filaments, pro-moting the assembly of filaments and
preventing their depolymerization. This increase in the stability of
mi-crofilaments results in disruption of mitosis and cyto-toxicity and disrupts
other normal microtubular func-tions, such as axonal transport in nerve fibers.
The major mechanism of
resistance that has been identified for paclitaxel is transport out of tumor
cells, which leads to decreased intracellular drug accumula-tion. This form of
resistance is mediated by the mul-tidrug transporter P-glycoprotein.
Paclitaxel’s large volume of
distribution indicates sig-nificant tissue binding. The drug is extensively
metabo-lized by the liver, and doses must be reduced in patients with abnormal
liver function or with extensive liver metastases. Very little of the drug is
excreted in the urine.
Paclitaxel is among the most
active of all anticancer drugs, with significant efficacy against carcinomas of
the breast, ovary, lung, head, and neck. It is combined with cisplatin in the
therapy of ovarian and lung carcinomas and with doxorubicin in treating breast
cancer.
Myelosuppression is the major
side effect of pacli-taxel. Alopecia is common, as is reversible dose-related
peripheral neuropathy. Most patients have mild numb-ness and tingling of the
fingers and toes beginning a few days after treatment. Mild muscle and joint
aching also may begin 2 or 3 days after initiation of therapy. Nausea is
usually mild or absent. Severe hypersensitivity reac-tions may occur.
Cardiovascular side effects, consisting of mild hypotension and bradycardia,
have been noted in up to 25% of patients.
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