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 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
Imatinib given with simvastatin increases simvastatin levels about
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.)