Targeted therapies

Targeted therapies

A groundbreaking approach to anticancer therapies involves targeting proteins associated with the growth patterns of specific types of cancer. Drugs used for this new approach to cancer treatment include:

• bortezomib
• gefitinib
• imatinib.

Pharmacokinetics

Bortezomib isn’t absorbed orally and must be given I.V. It’s extensively distributed into body tissues and metabolized by the liver.

Gefitinib is available in an oral form, and about half of the dose is absorbed. The drug is widely distributed in tissues. It undergoes hepatic metabolism with minimal urinary excretion.

Imatinib is also available in an oral form and is almost completely absorbed. It’s 95% bound to plasma proteins and is extensively metabolized by the liver. The half-life of imatinib is about 15 hours.

Pharmacodynamics

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 mechanisms and leads to cell death.

Warning!

Adverse reactions to topoisomerase I inhibitors

Common reactions

The more common adverse reactions to topo-isomerase I inhibitors, particularly irinotecan, include:

• diarrhea (possibly severe)
• abdominal cramps
• hair loss or thinning
• increased sweating and production of saliva
• nausea, vomiting, and loss of appetite
• tiredness
• watery eyes.

Additional reactions

Occasionally, these reactions may occur:

• mouth sores and ulcers
• muscle cramps
• rashes, which may be itchy
• significant myelosuppression, especially with topotecan (rare)
• temporary effects on liver function test results.

Too much of this…

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.

…too many of those

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 triphosphate’binding domain of the BCR-ABL protein, effectively shutting down the abnormal WBC production.

Pharmacotherapeutics

Bortezomib is used to treat multiple myeloma that has relapsed after standard chemotherapy.

Gefitinib is used as a single agent for patients with non’small-cell lung cancer that hasn’t responded to two standard chemotherapy regimens.

Imatinib is used to treat chronic myeloid leukemia, acute lymphoid leukemia, and GI stomal tumors.

Drug interactions

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, diltiazem, fluoxetine, verapamil, zafirlukast, and zileuton) or induce cytochrome CYP3A4 (such as amiodarone, carbamazepine, nevirapine, 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 elevations in the International Normalized Ratio, increasing the risk of bleeding.
• Clarithromycin, erythromycin, itraconazole, and ketoconazole, when taken with imatinibor may increase imatinib plasma levels.
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• 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 blockers, and certain HMG-CoA reductase inhibitors. 

Warning!

Adverse reactions to targeted therapies

Patients should avoid becoming pregnant while taking bortezomib, gefitinib, or imatinib because in animal studies these drugs crossed the placental barrier, causing fetal harm and death.

There are also adverse reactions specific to each therapy.

Bortezomib

• Fatigue, malaise, weakness, nausea, diarrhea, appetite loss, constipation, pyrexia, and vomiting (most common reactions)
• Peripheral neuropathy, headache, low blood pressure, liver toxicity, thrombocytopenia, renal toxicity, and cardiac toxicity, such as arrhythmias, heart failure, myocardial ischemia and infarction, pulmonary edema, and pericardial effusion (less common reactions)

Gefitinib

• Rash, diarrhea, and abnormal eyelash growth
• Lung and liver damage

Imatinib

• Periorbital and lower limb edema, possibly resulting in pulmonary edema, effusions, and heart or renal failure
• Nausea, vomiting, liver function abnormalities, and myelosuppression (especially neutropenia and thrombocytopenia)

Unclassifiable antineoplastic drugs

Many other antineoplastic drugs can’t be included in existing classifications. These drugs include:

• arsenic trioxide
• asparaginases
• procarbazine
• hydroxyurea
• interferon
• aldesleukin
• altretamine
• paclitaxel (taxane)
• docetaxel (taxane).