Targeted therapies
A groundbreaking approach to anticancer therapies
involves tar-geting proteins associated with the growth patterns of specific
types of cancer. Drugs used for this new approach to cancer treat-ment include:
·
bortezomib
·
gefitinib
·
imatinib.
Bortezomib isn’t absorbed orally and must be given I.V.
It’s exten-sively distributed into body tissues and metabolized by the liver.
·
Gefitinib is available in an oral form, and about half of
thedose is absorbed. The drug is widely distributed in tissues. It un-dergoes hepatic
metabolism with minimal urinary excretion.
·
Imatinib is also available in an oral form and is almost
com-pletely absorbed. It’s 95% bound to plasma proteins and is exten-sively
metabolized by the liver. The half-life of imatinib is about 15 hours.
Bortezomib inhibits proteosomes, which are
involved in integral cell-cycle function and promote tumor growth. Proteolysis
by bortezomib results in disruption of the normal homeostatic mech-anisms and
leads to cell death.
Gefitinib inhibits the epidermal growth factor
receptor-1 tyrosine kinase, which is overexpressed in such cancers as
non–small-cell lung cancer. This inhibition blocks signaling pathways for
growth, survival, and metastasis of cancer.
In patients with chronic myeloid leukemia, the
BCR-ABL protein stimulates other tyrosine kinase proteins, causing an
abnormally high production of WBCs. Imatinib binds to the adenosine
triphos-phate–binding domain of the BCR-ABL protein, effectively shut-ting down
the abnormal WBC production.
Bortezomib is used to treat multiple myeloma that
has relapsed af-ter standard chemotherapy.
·
Gefitinib is used as a single agent for patients with non–small-cell
lung cancer that hasn’t responded to two standard chemother-apy regimens.
·
Imatinib is used to treat chronic myeloid leukemia, acute lym-phoid
leukemia, and GI stomal tumors.
Bortezomib, gefitinib, and imatinib have been
associated with some drug interactions.
·
Bortezomib when taken with drugs that inhibit cytochrome CYP3A4 (such as
amiodarone, cimetidine, erythromycin, dilti-azem, fluoxetine, verapamil,
zafirlukast, and zileuton) or induce cytochrome CYP3A4 (such as amiodarone,
carbamazepine, nevir-apine, phenobarbital, phenytoin, and rifampin), could
cause either toxicities or reduced efficacy of these drugs.
·
Bortezomib when taken with oral hypoglycemics could cause hypoglycemia
and hyperglycemia in patients with diabetes.
·
Plasma levels of gefitinib and imatinib are reduced, sometimes
substantially, when these drugs are given with carbamazepine, dexamethasone,
phenobarbital, phenytoin, rifampin, or St. John’s wort.
·
High doses of ranitidine with sodium bicarbonate when taken with
gefitinib reduce gefitinib levels.
·
Administration of gefitinib or imatinib with warfarin causes ele-vations
in the International Normalized Ratio, increasing the risk of bleeding.
·
Clarithromycin, erythromycin, itraconazole, and ketoconazole, when taken
with imatinibor may increase imatinib plasma levels.
·
Carbamazepine, dexamethasone, phenobarbital, phenytoin, or rifampin
given with imatinib may increase metabolism of imatinib and decrease imatinib
level.
·
Imatinib given with simvastatin increases simvastatin levels about
threefold.
·
Imatinib increases plasma levels of other CYP3A4-metabolized drugs, such
as triazolo-benzodiazepines, calcium channel block-ers, and certain HMG-CoA
reductase inhibitors. (See Adverse
re-actions to targeted therapies.)
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