DRUG STUDY AND INFORMATION FORM Generic Name: Doxorubicin Trade Name: Adriamycin, Doxil (liposomal form) Drug

Class: Anthracyclines and Anthracenediones (Antibiotics) Structure/Chemistry: Possess a tetracycline ring structure attached to a sugar, daunosamine, with quinone and hydroquinone moieties on adjacent rings that permit the gain and loss of electrons.

Pharmacodynamics

Mechanism of Action: Intercalates with DNA, directly affecting transcription and translation. Forms a tripartite complex with topoisomerase II and DNA and prevents re-ligation of doublestranded breaks made by topoisomerase II which leads to apoptosis. Also generates free radicals by formation of semiquinone radical intermediates from quinone groups that react with O2 to produce superoxide anion radicals (increased radical production in combination with iron).

Pharmacologic Effects: DNA damage through inhibition of re-ligation by topoisomerase II. Apoptosis due to p53 and caspases.

Drug Resistance or Tolerance: Overexpression of transcription-linked DNA repair, multidrug resistance, MRP (Multidrug Resistance-associated Proteins) transporter family, breast cancer resistance protein, increased glutathione peroxidase activity, decreased activity or mutation of topoisomerase II, and enhanced ability to repair DNA strand breaks.

Pharmacokinetics

Absorption: IV administration of 60-75 mg/m2 as a single rapid IV infusion that is repeated after 21 days. Doxil (liposomal form) is given by IV in a dose of 20 mg/m2 over 60 mins every 3 weeks for treatment of AIDS-related Kaposi sarcoma, 50 mg/m2 every 4 weeks for ovarian cancer, and 30 mg/m2 on day 4 of each 21-day cycle for multiple myeloma (in combination with Bortezomib). Distribution: Rapidly enters heart, kidneys, lungs, liver, and spleen. Does not cross bloodbrain barrier.

Elimination: t1/2 of 30 hours. Eliminated by metabolic conversion to a variety of aglycones and other inactive products. Biliary excretion. Delayed in presence of hepatic dysfunction.

Metabolism: All anthracyclines are converted to an active alcohol intermediate.

Adverse Side Effects/Toxicity: High doses associated with cardiac toxicity subsequent to free radical generation (protection against via iron chelators [Dexrazoxane]), bone marrow suppression, leukopenia, thrombocytopenia, anemia, stomatitis, mucositis, diarrhea, alopecia, and severe local toxicity in irradiated tissues. Two forms of cardiomyopathy: acute (abnormal electrocardiographic changes) and chronic (dose-related, congestive heart failure). Avoid extravasation. Drug Interactions:

Therapeutic uses: Multiple myeloma, ovarian cancer, AIDS-related Kaposi sarcoma, malignant lymphomas (in combination with cyclophosphamide and vinca alkaloids), adjuvant and metastatic carcinoma of the breast, and other human solid tumors

Miscellaneous: Derived from Streptomyces peucetius var. caesius. May impart red color to urine.