Application of vitamin D and vitamin D analogs in acute myelogenous leukemia.
Acute myeloid leukemia (AML) is characterized by the accumulation of malignant, transformed immature hematopoietic myeloid precursors that have lost their ability to differentiate and proliferate normally. Current treatment for AML requires intensive cytotoxic chemotherapy and results in significant morbidity and mortality, especially in older patients. Effective and better-tolerated treatment is urgently needed. Studies have shown that 1α,25-dihydroxyvitamin D3 (1,25-D3, active VD3) or vitamin D analogs (VDAs) can potently differentiate AML cells in vitro and ex vivo, which led to early clinical trials in AML and myelodysplastic syndrome patients. However, one major limiting factor in the clinical application of active VD3 or VDAs is the supraphysiologic dose required, which results in systemic hypercalcemia. Several important questions (i.e., dosage, method of delivery, metabolism of 1,25-D3 in situ, systemic hypercalcemia, and mechanisms of action of combination treatment) have to be addressed before vitamin D treatment can be applied to the clinical setting. This review focuses on 1,25-D3's mechanism of action in AML, preclinical data, and clinical trial outcomes, with an emphasis on major roadblocks to successful trials and suggestions for future directions.
Division of Hematology/Oncology, Loma Linda University School of Medicine, Loma Linda, CA, USA. Electronic address: hcao@llu.edu.
Huynh
H
Cao
Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA, USA.
Yi
Y
Xu
Biospecimen Laboratory, Loma Linda University Cancer Center, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Rosalia
R
de Necochea-Campion
Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA, USA.
David J
DJ
Baylink
Division of Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
Kimberly J
KJ
Payne
Department of Medicine, Division of Regenerative Medicine, Loma Linda University, Loma Linda, CA, USA.
Xiaolei
X
Tang
Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Christina
C
Ratanatharathorn
Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Yong
Y
Ji
Biospecimen Laboratory, Loma Linda University Cancer Center, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Saied
S
Mirshahidi
Division of Hematology/Oncology, Loma Linda University School of Medicine, Loma Linda, CA, USA.
Chien-Shing
CS
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D044127:Epigenesis, Genetic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016896:Treatment Outcome; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014807:Vitamin D