Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. It acts by binding to DNA, which results in single-and double-strand breaks following free radical formation, and inhibition of DNA biosynthesis. The fragmentation of DNA is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations. Bleomycin is a cell cycle– specific drug that causes accumulation of cells in the G2 phase of the cell cycle.
Bleomycin is indicated for the treatment of Hodgkin’s and non-Hodgkin’s lymphomas, germ cell tumor, head and neck cancer, and squamous cell cancer of the skin, cervix, and vulva. One advantage of this agent is that it can be administered subcutaneously, intramuscularly, or intravenously. Elimination of bleomycin is mainly via renal excretion, and dose modification is recommended in patients with renal dysfunction.
Pulmonary toxicity is dose-limiting for bleomycin and usually presents as pneumonitis with cough, dyspnea, dry inspiratory crackles on physical examination, and infiltrates on chest x-ray.
The incidence of pulmonary toxicity is increased in patients older than 70 years of age, in those who receive cumulative doses greater than 400 units, in those with underlying pulmonary disease, and DRUGS in those who have received prior mediastinal or chest irradiation. A large number of anti-cancer drugs that do not fit traditional In rare cases, pulmonary toxicity can be fatal. Other toxicities are categories have been approved for clinical use; they are listed in listed in Table 54–4. Table 54–5.
TABLE 54–5 Miscellaneous anti-cancer drugs: Clinical activity and toxicities.
1See text for acronyms.
Imatinib is an inhibitor of the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP. It is indicated for the treatment of chronic myelogenous leukemia (CML), a pluripotent hematopoietic stem cell disorder characterized by the t(9:22) Philadelphia chromosomal translocation. This translocation results in the Bcr-Abl fusion protein, the causative agent in CML, and is present in up to 95% of patients with this disease. This agent also inhibits other receptor tyrosine kinases for platelet-derived growth factor receptor (PDGFR), and c-kit.
Imatinib is well absorbed orally, and it is metabolized in the liver, with elimination of metabolites occurring mainly in feces via biliary excretion. This agent is approved for use as first-line therapy in chronic phase CML, in blast crisis, and as second-line therapy for chronic phase CML that has progressed on prior IFN-α therapy. Imatinib is also effective in the treatment of gastrointestinal stromal tumors (GIST) expressing the c-kit tyrosine kinase. The main adverse effects are listed in Table 54–5.
Dasatinib is an oral inhibitor of several tyrosine kinases, including Bcr-Abl, Src, c-kit, and PDGFR-α. It differs from imatinib in that it binds to the active and inactive conformations of the Abl kinase domain and overcomes imatinib resistance resulting from mutations in the Bcr-Abl kinase. It is approved for use in CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with resistance or intolerance to imatinib therapy.