Leukemia treatment, specific agents

Alemtuzumab (campath-lH) is a humanized monoclonal antibody specific for the CDw52 antigen, present on cell membranes of lymphocytes and monocytes. It has been used for treatment of patients with rheumatoid arthritis and vasculitis, is being investigated for the treatment of chronic lymphocytic leukemia, and has been used to deplete circulating lymphocytes in patients with multiple sclerosis (1). In 2001, alemtuzumab was approved in Europe for the treatment of chronic B cell lymphocytic leukemia that had been treated previously with alkylating agents and was refractory to fludarabine (2). It has also been used for induction of immunosuppression/tolerance in liver transplant recipients (3,4) and kidney/pancreas transplant recipients (5). 

There is now compelling evidence from the number of retinoids in the clinic and in clinical studies (Table 12.1) that these molecules exhibit efficacy in human diseases. The use of ATRA for the treatment of acute promyelocytic leukemia is considered a successful therapy in our view. It is the hope that the application of retinoids, most probably more receptor specific retinoids/rexinoids, in combination with other chemotherapeutic agents, will lead to broad clinical utility in many diseases. We anticipate that the retinoid field will continue to expand as researchers gain more information about new levels of retinoid/rexinoid biology and their relevance to human diseases. 

The prototype molecularly targeted therapeutic agent is imatinib, an inhibitor of the Bcr-Abl tyrosine kinase. This oncogenic kinase is produced by translocation of the Bcr locus on chromosome 9 to the c-Abl tyrosine kinase on chromosome 11, termed the Philadelphia chromosome because of its discovery in 1960 at the University of Pennsylvania School of Medicine by Peter Nowell and David Hungerford from the Institute for Cancer Research [9]. It was later demonstrated in 1973 by Janet Rowley that the Philadelphia translocation was responsible for a specific form of leukemia, chronic myelogenous leukemia (CML) [10], In 2001, imatinib was approved for treatment of CML patients, and produced remarkable results with more than 92% patients achieving 14-month progression-free survival on imatinib as a monotherapy. 

As it possesses the potential to cross the blood-brain-barrier, carmustine is employed specifically for brain tumours and other tumours, for instance leukemias, which have metastasized to the brain. A combination of carmustine and prednisone is used for the treatment of multiple myeloma. As a secondary therapy it is frequently employed in conjunetion with other antineoplastic agents for lymphomas and Hodgkin s disease. 

Narciclasine (22) halts protein synthesis by blockage of peptide-bond formation on the 60-S ribosomal subunit. The effect is specific for eucaryotic cells. Narciclasine inhibits Rauscher virus NIH/3T3 (Wink, 1993). Lycorine (8) blocks mitosis in the broad bean (Viciafaba). The mechanism appears to be related to inhibition of protein synthesis (Suffness and Cordell, 1985). Pretazettine (15) has been used in combination with DNA-binding and alkylating agents in the treatment of the Rauscher leukemia virus (Cordell, 1981 Martin, 1987). This alkaloid inhibits purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myelo-... 

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