TPA for treatment of AML

Acute myelogenous leukemia (AML) is an aggressive disease that generally warrants urgent and intensive therapy. The average patient age at AML diagnosis is 64 to 68 years and patients over the age of 60 treated with standard chemotherapy are cured of their disease less than 20 percent of the time. Patients who develop AML after an antecedent hematologic disorder or prior leukemogenic chemotherapy/radiation therapy have similarly poor outcomes as do patients whose disease is associated with specific cytogenetic and clinical features. Hence, most patients diagnosed with AML have patient and/or disease related features that are associated with a very poor prognosis. For patients with relapsed disease, no standard non-transplant therapy has demonstrated the capacity for cure. For these patients, AML is often a fatal disease. New approaches to therapy are needed.

TPA is an acronym for 12-O-tetradecanoylphorbol-13-acetate, a naturally occurring phorbol ester isolated from croton oil (Crotum tiglium)). TPA has been widely studied as a differentiating agent (1-20) a cytokine inducer (21-30). Phorbol esters activate protein kinase (pkc) and modulate the activity of multiple downstream cell signaling pathway (37-42).

The activity of TPA as a differentiating agent has been established by studies of HL-60 human promyelocytic cells and primary human leukemia cells obtained from patients. TPA induces a broad spectrum of biologic effects that provide a basis for suggesting that it may be useful in AML. At the cellular level, many of these effects may be mediated by protein kinase C. Protein kinase C is a family of phospholipid and calcium dependent isozymes that are activated by diacylglycerol. TPA appears to be able to activate protein kinase C in the absence of diacylglycerol. The targets of phosphorylation are incompletely defined but appear to result in the activation of several processes involved in cellular proliferation, differentiation, mitogenesis, neurotransmission and hormone secretion. Two well characterized transcription activation/repression pathways regulated by NF-kB and AP-1 transcription complexes appear to be regulated by protein kinase C (43-44).

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