Retinoic acid and its rearranged receptor in the treatment of acute promyelocytic leukemia.
APL is a unique clinical example where a defined molecular genetic defect appears involved in both the pathogenesis and treatment of a human leukemia. The consistent finding that RA induces remissions in APL is especially notable, since treatment involves an oral formulation of RA. The clinical responses are linked to leukemic cell maturation, suggesting a noncytotoxic mechanism of RA action. This provides a rationale for combining cytotoxic and cytodifferentiation agents in future clinical trials. Despite high initial CR rates with continuous RA therapy, relapses frequently occur. Pharmacologic mechanisms of resistance to RA therapy are implicated in clinical resistance. Future work will explore if this resistance can be overcome and how genetic mechanisms contribute to clinical RA resistance in APL. The exciting convergence of clinical and basic information in PL has led to new insights into the molecular nature of this leukemia. The discovery that RAR-alpha is rearranged in the t(15,17) provides an opportunity to study how this rearrangement is involved in oncogenesis and treatment response in APL. The application of RT-PCR assays for this molecular rearrangement will be useful in the diagnosis and subsequent tailoring of postremission therapy in APL. Whether APL serves as a paradigm for cytodifferentiation therapy remains to be seen. However, it is encouraging that 13-cis-retinoic acid in combination with alpha interferon is an active therapy in squamous cell carcinomas of the cervix and skin. Although the mechanisms responsible for these clinical responses are unknown, they highlight the need to learn how RA works and when it should be used to treat cancer patients.
Miller
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Dmitrovsky
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D001483:Base Sequence; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics; D015321:Gene Rearrangement; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000235:genetics; D018168:Receptors, Retinoic Acid; D014212:Tretinoin / Q000627:therapeutic use*
D002352:Carrier Proteins; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin