Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations.
We describe in vitro studies and a therapeutic trial of retinoic acid (RA) in a patient with acute promyelocytic leukemia (APL) refractory to chemotherapy. Bone marrow promyelocytes from the patient, prior to RA, matured morphologically in liquid culture with RA (97% maturing myeloid cells compared with 26% in control cultures at 7 days). RA-cultured cells displayed leukocyte alkaline phosphatase activity and cytoplasmic maturation (by electron microscopy). Retinoic-acid-treated cells, compared to controls, demonstrated increased functional maturation, with phagocytosis of opsonized zymosan (90% versus 10%) and production of superoxide (measured by nitroblue tetrazolium reduction) in response to phorbol ester, opsonized zymosan, or the chemotaxin F-met-leu-phe. There was no evidence of active proliferation in the cultures. RA-treated cells continued to show 15;17 chromosomal translocation after 7 days in culture. The patient was treated with oral 13-cis-retinoic acid (100 mg/sq m/day) for 13 days. During that time, the peripheral white blood count rose from 300 cu mm to 6,700 cu mm, and the maturing myeloid cell count rose from 54 cu mm to 3,800 cu mm. Bone marrow maturing cells increased from 1.8% to 8.0%. Despite the increasing number of maturing myeloid cells, the patient died on day 13 from disseminated candidiasis. These data confirm that RA induces maturation of leukemic promyelocytes in vitro and suggest that similar maturation is achievable in vivo. We suggest that oral retinoic acid may be a useful adjunct in the treatment of APL.
D000328:Adult; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D002478:Cells, Cultured; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy* / Q000648:ultrastructure; D007958:Leukocyte Count; D008297:Male; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*
D014212:Tretinoin