Mohamad A Hussein1. 1. Myeloma Research Program, Cleveland Clinic, OH 44195, USA. mah@runbox.com
Abstract
BACKGROUND: Several reports on the use of arsenic trioxide (ATO), mainly in acute promyelocytic leukemia, have led to a renewed interest in ATO in the management of malignancies, especially those of hematologic origin such as multiple myeloma (MM). MM remains an incurable disease, with median survival rates of 4-6 years. Thus, newer treatments with good safety profiles are needed to improve the quality of responses, prolong progression, and increase overall survival. METHOD: The current state of the art regarding the role of ATO in the management of MM and the rationale for this consideration is reviewed. RESULTS: Preclinical evidence suggests that one of the mechanisms in which ATO exerts its antimyeloma effect is by immunologic mechanisms. One such mechanism appears to be achieved by a marked increase in lymphokine-activated killer (LAK)-mediated killing and up-modulation of CD38 and CD54, two molecules involved in cell-cell interactions. Two phase II trials have shown that the drug appears to be clinically effective. CONCLUSIONS: With the improved understanding of the interaction between the myeloma cell and its microenvironment as well as the cytokine support system, it does not appear than any particular agent will be able to control the disease permanently. In the clinical arena, the next generation of studies will be designed to combine different molecules to take advantage of non-overlapping toxicities and to compromise the extensive and redundant myeloma support system, thus controlling the disease in a chronic phase.
BACKGROUND: Several reports on the use of arsenic trioxide (ATO), mainly in acute promyelocytic leukemia, have led to a renewed interest in ATO in the management of malignancies, especially those of hematologic origin such as multiple myeloma (MM). MM remains an incurable disease, with median survival rates of 4-6 years. Thus, newer treatments with good safety profiles are needed to improve the quality of responses, prolong progression, and increase overall survival. METHOD: The current state of the art regarding the role of ATO in the management of MM and the rationale for this consideration is reviewed. RESULTS: Preclinical evidence suggests that one of the mechanisms in which ATO exerts its antimyeloma effect is by immunologic mechanisms. One such mechanism appears to be achieved by a marked increase in lymphokine-activated killer (LAK)-mediated killing and up-modulation of CD38 and CD54, two molecules involved in cell-cell interactions. Two phase II trials have shown that the drug appears to be clinically effective. CONCLUSIONS: With the improved understanding of the interaction between the myeloma cell and its microenvironment as well as the cytokine support system, it does not appear than any particular agent will be able to control the disease permanently. In the clinical arena, the next generation of studies will be designed to combine different molecules to take advantage of non-overlapping toxicities and to compromise the extensive and redundant myeloma support system, thus controlling the disease in a chronic phase.
Authors: Shannon M Matulis; Alejo A Morales; Lucy Yehiayan; Claire Croutch; Delia Gutman; Yong Cai; Kelvin P Lee; Lawrence H Boise Journal: Mol Cancer Ther Date: 2009-05-05 Impact factor: 6.261