Skip to main content

Tretinoin

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Use in the Management of Acute Promyelocytic Leukaemia

Drugs volume 50, pages 897–923 (1995)Cite this article

Abstract

Synopsis

Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation.

Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient’s response to treatment and to help detect the presence of residual or recurrent disease.

The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management.

In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia.

Pharmacodynamic Properties

Acute promyelocytic leukaemia is characterised by a unique t(15;17) chromosomal translocation between the retinoic acid receptor-alpha (RAR-α) gene on chromosome 17 and a gene known as PML (promyelocyte leukaemia) on chromosome 15. The resultant PML/RAR-α fusion protein appears to be responsible for the failure of promyelocytes to differentiate and explains at a molecular level why only leukaemic cells that express this protein are sensitive to tretinoin. Thus, patients with variant cytogenetic abnormalities respond poorly to tretinoin.

Tretinoin induces terminal differentiation in a number of haemopoietic precursor cell lines as well as in cells from patients with acute promyelocytic leukaemia. The exact mechanism of action of tretinoin remains to be fully elucidated, but drug exposure or treatment is associated with progressive morphological and functional maturation of leukaemic cells and the appearance of normal haemopoietic cells. In vitro sensitivity of acute promyelocytic leukaemia cells to tretinoin correlates well with the clinical response observed in patients during treatment with this agent. Additive or synergistic effects have been observed in vitro when tretinoin was combined with some putative differentiating agents, such as recombinant human interferon-α, but results require confirmation in vivo.

Pharmacokinetic Properties

The oral bioavailability of tretinoin is approximately 50% and, after single dose administration, plasma drug concentrations remain within the range required for in vitro differentiation of acute promyelocytic leukaemia cells for about 4 hours.

Tretinoin is distributed rapidly and extensively to tissues but has not been detected in cerebrospinal fluid. Repeated dose administration results in a marked reduction in plasma drug concentration and area under the plasma concentration-time curve which is associated with relapse in treated patients.

Tretinoin undergoes oxidative metabolism via the cytochrome P450 enzyme system in the liver, glucuronide conjugation and elimination in urine and bile. Tretinoin appears to undergo capacity-limited (saturable) elimination with a terminal elimination half-life of less than 1 hour.

Therapeutic Use

Results from 1 comparative and several noncomparative trials indicate that tretinoin (most commonly 45 mg/m2/day) induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. The duration of drug treatment needed to induce remission has varied widely between 8 and 119 days. In newly diagnosed patients, tretinoin followed by intensive chemotherapy (daunorubicin and cytosine arabinoside) significantly reduced the 1-year relapse rate (13 vs 41%) and increased 2-year event-free (68 vs 23%) and overall survival (81 vs 51%) compared with the same chemotherapy regimen alone, despite similar rates of complete remission (91 vs 81%). In noncomparative studies, no significant differences in drug efficacy were evident on the basis of disease status, although definitive conclusions are precluded by limited patient enrolments. Although resistance to tretinoin in most patients with acute promyelocytic leukaemia and a t(15;17) translocation is initially very low, it appears to be acquired rapidly and almost universally during continuous drug treatment.

Detection of the t(15;17) chromosomal translocation or the PML/RAR-α fusion protein correlates highly with the presence of disease and the occurrence of relapse. Induction of remission with tretinoin and/or chemotherapy is associated with progressive disappearance of these cytogenetic abnormalities, although reverse transcription polymerase chain reaction (RT-PCR) tests indicate that tretinoin alone is usually unable to totally eradicate the leukaemic clone. This finding is in keeping with clinical observations that remissions induced by tretinoin alone are generally brief in duration unless followed by consolidation chemotherapy or bone marrow transplant. There is no convincing evidence that tretinoin is useful for consolidation or maintenance therapy.

Tolerability

Compared with standard antineoplastic chemotherapy, which is cytotoxic to normal haemopoietic and leukaemic cells, tretinoin induces remission in patients with acute promyelocytic leukaemia without causing bone marrow hypoplasia or exacerbation of the frequently occurring haemorrhagic syndrome. In fact, many trials have reported that bleeding complications associated with this disease resolve within 4 to 6 days of patients starting drug treatment.

A potentially serious consequence of tretinoin therapy is the development of retinoic acid syndrome. This syndrome, which is characterised by fever, respiratory distress, interstitial pulmonary infiltrates, pleural effusions and weight gain, may occur in up to 25% of patients and can be fatal if not promptly recognised and treated. It has been successfully managed with high dose corticosteroids and/or addition of standard chemotherapy to tretinoin therapy, although additional data are needed to determine the efficacy and appropriate use of these strategies.

In common with other retinoids, adverse events with tretinoin often involve the skin and mucous membranes. Dryness of the skin, nasal and/or other mucosal membranes and/or cheilitis occur in 24 to 65% of patients but respond to symptomatic treatment. Similarly, headaches, bone pain and arthralgias are frequently reported but are alleviated by analgesics.

Children may be less tolerant of the adverse events associated with tretinoin, particularly those events related to the CNS (headache and pseudotumour cerebri).

Increased levels of triglycerides, serum creatinine and/or hepatic enzymes are observed but do not usually necessitate interruption or withdrawal of tretinoin therapy.

Dosage and Administration

The recommended oral dose of tretinoin is 45 mg/m2/day in all patients with acute promyelocytic leukaemia, including children and the elderly. Treatment is continued for 30 to 90 days until complete remission has been achieved, at which time consolidation chemotherapy, such as daunorubicin and cytosine arabinoside, should be initiated.

If significant elevation in white blood cell count is present or occurs within 15 days of treatment the addition of chemotherapy is recommended. High dose corticosteroids should be administered for at least 3 days to patients who develop symptoms of retinoic acid syndrome.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 49.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. Br J Haematol 1976; 33: 451–8.

    PubMed  CAS  Google Scholar 

  2. Dulaney AM, Murgatroyd RJ. Use of trans-retinoic acid in the treatment of acute promyelocytic leukemia. Ann Pharmacother 1993 Feb; 27: 211–4.

    Google Scholar 

  3. Rousselot P, Hardas B, Patel A, et al. The PML-RARα gene product of the t(15;17) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells. Oncogene 1994 Feb; 9: 545–51.

    Google Scholar 

  4. Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York study. Ann Intern Med 1994 Feb 15; 120: 278–86.

    PubMed  CAS  Google Scholar 

  5. Lo-Coco F, Diverio D, Pandolfi PP, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet 1992 Dec 12; 340: 1437–8.

    PubMed  CAS  Google Scholar 

  6. Miller Jr WH, Kakizuka A, Frankel SR, et al. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor a clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1992 Apr 1; 89: 2694–8.

    PubMed  CAS  Google Scholar 

  7. Cheson BD. The maturation of differentiation therapy. N Engl J Med 1992 Aug 6; 327: 422–4.

    PubMed  CAS  Google Scholar 

  8. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994 Jan 1; 83: 10–25.

    PubMed  CAS  Google Scholar 

  9. van Bockstaele DR, Lenjou M, Snoeck H-W, et al. Direct effects of 13-cis and all-trans retinoic acid on normal bone marrow (BM) progenitors: comparative study on BM mononucleur cells and on isolated CD34+ BM cells. Ann Hematol 1993; 66: 61–6.

    PubMed  Google Scholar 

  10. Gratas C, Menot ML, Dresch C, et al. Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow. Leukemia 1993 August; 17 (8): 1156–62

    Google Scholar 

  11. Trayner ID, Farzaneh F. Retinoid receptors and acute promyelocytic leukaemia. Eur J Cancer 1993; 29A (14): 2046–54

    PubMed  CAS  Google Scholar 

  12. Falk LA, De-Benedetti F, Lohrey N, et al. Induction of transforming growth factor-β1 (TGF-β1), receptor expression and TGF-β1 protein production in retinoic acid-treated HL-60 cells: possible TGF-β1-mediated autocrine inhibition. Blood 1991 Mar 15; 77: 1248–55.

    PubMed  CAS  Google Scholar 

  13. Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A 1980 May; 77: 2936–40.

    Google Scholar 

  14. Gezer S, Yasin Z, Imren S, et al. Changes observed in the growth fraction, labeling index, duration of S phase, and total cell cycle times of HL-60 cells as they undergo differentiation in response to retinoic acid. Cancer Res 1988 Nov 1; 48: 5989–94.

    PubMed  CAS  Google Scholar 

  15. Frey JR, Peck R, Bollag W. Antiproliferative activity of retinoids, interferon a and their combination in five human transformed cell lines. Cancer Lett 1991 May 24; 57: 223–7.

    PubMed  CAS  Google Scholar 

  16. Kohlhepp EA, Condon ME, Hamburger AW. Recombinant human interferon a enhancement of retinoic-acid-induced differentiation of HL-60 cells. Exp Hematol 1987 May; 15: 414–8.

    Google Scholar 

  17. Taoka T, Yamaoka G, Arai T, et al. Alkaline phosphatase activity in the human promyelocytic leukemia cell line, HL-60, induced by retinoic acid and recombinant human granulocyte colony-stimulating factor. Leuk Res 1993 Aug; 17: 695–8.

    Google Scholar 

  18. Preisler HD, Gopal V, Banavali SD, et al. Multiparameter assessment of the cell cycle effects of bioactive and cytotoxic agents. Cancer Res 1992 August 1; 52: 4090–5.

    PubMed  CAS  Google Scholar 

  19. Di Noto R, Schiavone EM, Ferrara F, et al. All-trans retinoic acid promotes a differential regulation of adhesion molecules on acute myeloid leukaemia blast cells. Br J Haematol 1994; 88: 247–55.

    PubMed  Google Scholar 

  20. Dubois C, Schlageter MHL, Degentile A, et al. Modulation of IL-8, IL-1 β, and G-CSF secretion by all-trans retinoic acid in acute promyelocytic leukemia. Leukemia 1994 Oct; 8: 1750–7.

    Google Scholar 

  21. Dubois C, Schlageter MH, deGentile A, et al. Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells. Blood 1994 Jun 1; 83: 3264–70.

    PubMed  CAS  Google Scholar 

  22. Tobler A, Munker R, Heitjan D, et al. In vitro interaction of recombinant tumor necrosis factor alpha and all-transretinoic acid with normal and leukemic hematopoietic cells. Blood 1987 Dec; 70: 1940–6.

    Google Scholar 

  23. Warrell Jr RP, Frankel SR, Miller Jr WH, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retmoic acid). N Engl J Med 1991 May 16; 324: 1385–93.

    PubMed  Google Scholar 

  24. Di Noto R, Schiavone EM, Lo Pardo C, et al. Adhesion molecules in acute promyelocytic leukemia: effects of in vitro exposure to ATRA [abstract G-21]. Leuk Lymphoma 1994; 13 Suppl. 1: 128.

    Google Scholar 

  25. Imaizumi M, Sato A, Koizumi Y, et al. Potentiated maturation with a high proliferating activity of acute promyelocytic leukemia induced in vitro by granulocyte or granulocyte/macro-phage colony-stimulating factors in combination with all-trans retinoic acid. Leukemia 1994 Aug; 8: 1301–8.

    Google Scholar 

  26. Drach J, Zhao SR, Malavasi F, et al. Rapid induction of CD38 antigen on myeloid leukemia cells by all trans-retinoic acid. Biochem Biophys Res Commun 1993 Sep 15; 195: 545–50.

    PubMed  CAS  Google Scholar 

  27. Janick-Buckner D, Barua AB, Olson JA. Induction of HL-60 cell differentiation by water-soluble and nitrogen-containing conjugates of retinoic acid and retinol. FASEB J 1991 Mar 1; 5: 320–5.

    PubMed  CAS  Google Scholar 

  28. Falanga A, Consonni R, Marchetti M, et al. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by all-trans-retinoic acid. Leukemia 1994 Jan; 8: 156–9.

    Google Scholar 

  29. Falanga A, Iacoviello L, Evangelista V, et al. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid? Blood 1995 August 1; 86 (3): 1072–81.

    PubMed  CAS  Google Scholar 

  30. Qiao L, Pizzolo JG, Gorczyca W, et al. P145 expression during the cell cycle in HL-60 cell line and normal human lymphocytes: effects of camptothecin, vinblastine, cycloheximide, actinomycin D, retinoic acid and DMSO. Leuk Res 1993 Nov; 17: 991–7.

    Google Scholar 

  31. Tosi P, Visani G, Gibellini D, et al. All-trans retinoic acid and induction of apoptosis in acute promyelocytic leukemia cells. Leuk Lymphoma 1994 Aug; 14: 503–7.

    Google Scholar 

  32. Wu X, Shao G, Chen S, et al. Studies on the relationship between protein kinase C and differentiation of human promyelocytic leukemia cells induced by retinoic acid? Leuk Res 1989; 13 (10): 869–74.

    PubMed  CAS  Google Scholar 

  33. Bollag W. Retinoids and interferon: a new promising combination? Br J Haematol 1991 Oct; 79 Suppl 1: 87–91

    PubMed  CAS  Google Scholar 

  34. Yamaji Y, Natsumeda Y, Yamada Y, et al. Synergistic action of tiazofurin and retinoic acid on differentiation and colony formation of HL-60 leukemia cells? Life Sci 1990; 46 (6): 435–42.

    PubMed  CAS  Google Scholar 

  35. Matzner Y, Gavison R, Rachmilewitz EA, et al. Expression of granulocytic functions by leukemic promyelocytic HL-60 cells: differential induction by dimethylsulf oxide and retinoic acid. Cell Differ 1987 Sep; 21: 261–9.

    Google Scholar 

  36. Glasser L, Fiederlein RL, Shamdas GJ, et al. Functional characteristics of in vivo induced neutrophils after differentiation therapy of acute promyelocytic leukemia with all-trans-retinoic acid. Cancer 1994 Feb 15; 73: 1206–12.

    PubMed  CAS  Google Scholar 

  37. Itoh Y, Ohyashiki K, Ohtaka M, et al. All-trans-retinoic acid induced enrichment of functionally normal neutrophils in vivo in a patient with acute promyelocytic leukemia. Leukemia 1992 Aug; 6: 806–8.

    Google Scholar 

  38. Ohashi H, Ichikawa A, Takagi N, et al. Remission induction of acute promyelocytic leukemia by all-trans-retinoic acid: molecular evidence of restoration of normal hematopoiesis after differentiation and subsequent extinction of leukemic clone. Leukemia 1992 Aug; 6: 859–62.

    Google Scholar 

  39. Collins SJ, Robertson KA, Mueller L. Retinoic acid-induced granulocytic differentiation of HL-60 myeloid leukemia cells is mediated directly through the retinoic acid receptor (RAR-α). Mol Cell Biol 1990 May; 10: 2154–63.

    Google Scholar 

  40. Tohda S, Curtis JE, McCulloch EA, et al. Comparison of the effects of all-trans and cis-retinoic acid on the blast stem cells of acute myeloblastic leukemia in culture. Leukemia 1992 Jul; 6: 656–61.

    Google Scholar 

  41. Chomienne G, Ballerini P, Balitrand N, et al. All-trans retinoic acid in acute promyelocytic leukaemias. II. In vitro studies: structure-function relationship. Blood 1990 Nov 1; 76: 1710–7.

    PubMed  CAS  Google Scholar 

  42. Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 1981 Jun; 57: 1000–4.

    Google Scholar 

  43. Chomienne C, Balitrand N, Ballerini P, et al. All-trans retinoic acid modulates the retinoic acid receptor-α in promyelocytic cells. J Clin Invest 1991 Dec; 88: 2150–4.

    Google Scholar 

  44. Wu XZ, Wang WW, Zhou ZL, et al. Chromosome observations of acute promyelocytic leukemia treated with all-[itrans] retinoic acid? Hematol Pathol 1992; 6 (1): 25–9.

    PubMed  CAS  Google Scholar 

  45. Elliott S, Taylor K, White S, et al. Proof of differentiative mode of action of all-trans retinoic acid in acute promyelocytic leukemia using X-linked clonal analysis. Blood 1992 Apr 15; 79: 1916–9.

    PubMed  CAS  Google Scholar 

  46. LoCoco F, Pelicci PG, D’Adamo F, et al. Polyclonal hematopoietic reconstitution in leukemia patients at remission after suppression of specific gene rearrangements [see comments]. Blood 1993 Jul 15; 82: 606–12.

    CAS  Google Scholar 

  47. Chen Z-X, Xue Y-Q, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 1991 Sep 15; 78: 1413–9.

    PubMed  CAS  Google Scholar 

  48. Wu XZ, Wang XW, Qien XP, et al. Four years’ experience with the treatment of all-trans-retinoic acid in acute promyelocytic leukemia. Am J Hematol 1993 Jul; 43: 183–9.

    Google Scholar 

  49. Fenaux P, LeDeley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 1993 Dec 1; 82: 3241–9.

    PubMed  CAS  Google Scholar 

  50. Ohno R, Yoshida H, Fukutani H, et al. Multi-institutional study of all-trans-retinoic acid as a differentiation therapy of refractory acute promyelocytic leukemia. Leukaemia Study Group of the Ministry of Health and Welfare. Leukemia 1993 Nov; 7: 1722–7.

    Google Scholar 

  51. Sun G-L, Ouyang R-R, Chen S-J, et al. Treatment of acute promyelocytic leukemia with all-trans-retinoic acid — a 5-year experience. Chin Med J 1993 Oct; 106: 743–8.

    Google Scholar 

  52. Fenaux P, Castaigne S, Dombret H, et al. All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood 1992 Nov 1; 80: 2176–81.

    PubMed  CAS  Google Scholar 

  53. Miller Jr WH, Jakubowski A, Tong WP, et al. 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia? Blood 1995 June 1; 85 (11): 3021–7.

    PubMed  CAS  Google Scholar 

  54. Gianni M, Terao M, Zanotta S, et al. Retinoic acid and granulocyte colony-stimulating factor synergistically induce leukocyte alkaline phosphatase in acute promyelocytic leukemia cells. Blood 1994 Apr 1; 83: 1909–21.

    PubMed  CAS  Google Scholar 

  55. Lin J, Sartorelli AC. Stimulation by interferon of the differentiation of human promyelocytic leukemia (HL-60) cells produced by retinoic acid and actinomycin D. J Interferon Res 1987 Aug; 7: 379–87.

    Google Scholar 

  56. Nakamaki T, Sakashita A, Hino KI, et al. Difference in effects of interferon-α and interferon-γ on the induction of differentiation of retinoic acid-treated acute myeloid leukemia cells in primary culture? Leuk Res 1990; 14 (9): 785–94.

    PubMed  CAS  Google Scholar 

  57. Grant S, Bhalla K, Weinstein B, et al. Recombinant human interferon sensitizes resistant myeloid leukemic cells to induction of terminal differentiation. Biochem Biophys Res Commun 1985 Jul 16; 130: 379–88.

    PubMed  CAS  Google Scholar 

  58. Chomienne C, Balitrand N, Degos L, et al. 1-B-D arabinofuranosyl cytosine and all-trans retinoic acid in combination accelerates and increases monocyte differentiation of myeloid leukemic cells. Leuk Res 1986; 10: 631–6.

    PubMed  CAS  Google Scholar 

  59. Chen Z-X, Breitman TR. Tributyrin: a prodrug of butyric acid for potential clinical application in differentiation therapy. Cancer Res 1994 Jul 1; 54: 3494–9.

    PubMed  CAS  Google Scholar 

  60. Momparler RL, Doré BT, Momparler LF. Effect of 5-aza-2′-deoxycytidine and retinoic acid on differentiation and C-myc expression in HL-60 myeloid leukemic cells. Cancer Lett 1990 Oct 8; 54: 21–8.

    PubMed  CAS  Google Scholar 

  61. Bunce CM, French PJ, Durham J, et al. Indomethacin potentiates the induction of HL60 differentiation to neutrophils, by retinoic acid and granulocyte colony-stimulating factor, and to monocytes, by vitamin D3. Leukemia 1994 Apr; 8 (4): 595–604

    PubMed  CAS  Google Scholar 

  62. Defacque H, Dornand J, Commes T, et al. Different combinations of retinoids and vitamin D3 analogs efficiently promote growth inhibition and differentiation of myelomonocytic leukemia cell lines. J Pharmacol Exp Ther 1994 Oct; 271: 193–9.

    Google Scholar 

  63. Doré BT, Uskokovìc MR, Momparler RL. Interaction of retinoic acid and vitamin-D3 analogs on HL-60 myeloid leukemic cells. Leuk Res 1993 Sep; 17: 749–57.

    Google Scholar 

  64. Bunce CM, Wallington LA, Harrison P, et al. Treatment of HL60 cells with various combinations of retinoids and 1 alpha, 25 dihydroxyvitamin D3 results in differentiation towards neutrophils or monocytes or a failure to differentiate and apoptosis. Leukemia 1995 March; 9 (3): 410–8

    PubMed  CAS  Google Scholar 

  65. Hassan HT, Rees J. Triple combination of retinoic acid plus actinomycin D plus dimethylformamide induces differentiation of human acute myeloid leukaemic blasts in primary culture. Cancer Chemother Pharmacol 1990 Apr; 26: 26–30.

    Google Scholar 

  66. Gillard EF, Solomon E. Acute promyelocytic leukaemia and the t(15;17) translocation. Semin Cancer Biol 1993 Dec; 4: 359–67.

    Google Scholar 

  67. Warrell RP Jr, de-The H, Wang ZY, et al. Acute promyelocytic leukemia. N Engl J Med 1993 Jul 15; 329: 177–89.

    PubMed  CAS  Google Scholar 

  68. Mu ZM, Chin KV, Liu JH, et al. PML, a growth suppressor disrupted in acute promyelocytic leukemia. Mol Cell Biol 1994 October; 14 (10): 6858–67

    PubMed  CAS  Google Scholar 

  69. Dyck JA, Maul GG, Miller Jr WH, et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 1994 Jan 28; 76: 333–43.

    PubMed  CAS  Google Scholar 

  70. Dermime S, Grignani F, Clerici M, et al. Occurrence of resistance to retinoic acid in the acute promyelocytic leukemia cell line NB4 is associated with altered expression of the pml/RARα protein. Blood 1993 Sep 1; 82: 1573–7.

    PubMed  CAS  Google Scholar 

  71. Dermime S, Grignani F, Rogaia D, et al. Acute promyelocytic leukaemia cells resistant to retinoic acid show further perturbation of the RARα signal transduction system. Leuk Lymphoma 1995 January; 16: 289–95.

    Google Scholar 

  72. Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993 Aug 13; 74: 423–31.

    PubMed  CAS  Google Scholar 

  73. Cortes JE, Kantarjian H, O’Brien S, et al. All-trans retinoic acid followed by chemotherapy for salvage of refractory or relapsed acute promyelocytic leukemia. Cancer 1994 Jun 15; 73: 2946–52.

    PubMed  CAS  Google Scholar 

  74. Chen SJ, Chen Z, Chen A, et al. Occurrence of distinct PML-RAR-alpha fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse transcriptase/polymerase chain reaction. Oncogene 1992 Jun; 7: 1223–32.

    Google Scholar 

  75. Guidez F, Huang W, Tong J-H, et al. Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RARα patient. Leukemia 1994 Feb; 8: 312–7.

    Google Scholar 

  76. Licht JD, Chomienne C, Goy A, et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17)? Blood 1995 February 15; 85 (4): 1083–94.

    PubMed  CAS  Google Scholar 

  77. Tsurugano S, Togawa A, Soda Y, et al. Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all-trans-retinoic acid [in Japanese]. Rinsho Ketsueki 1994 Jan; 35: 36–41.

    Google Scholar 

  78. Muindi JRF, Frankel SR, Huselton C, et al. Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Cancer Res 1992 Apr 15; 52: 2138–42.

    PubMed  CAS  Google Scholar 

  79. Lefebvre P, Thomas G, Gourmel B, et al. Pharmacokinetics of oral all-trans retinoic acid in patients with acute promyelocytic leukemia. Leukemia 1991 Dec; 5: 1054–8.

    Google Scholar 

  80. Smith MA, Adamson PC, Balis FM, et al. Phase I and pharmacokinetic evaluation of all-trans-retmoic acid in pediatric patients with cancer. J Clin Oncol 1992 Nov; 10: 1666–73.

    Google Scholar 

  81. Muindi J, Frankel SR, Miller Jr WH, et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid resistance in patients with acute promyelocytic leukemia. Blood 1992 Jan 15; 79: 299–303.

    PubMed  CAS  Google Scholar 

  82. Rigas JR, Francis PA, Muindi JRF, et al. Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole. J Natl Cancer Inst 1993 Dec 1; 85: 1921–6.

    PubMed  CAS  Google Scholar 

  83. Warrell Jr RP Retinoid resistance in acute promyelocytic leukemia: new mechanisms, strategies, and implications [editorial; comment]. Blood 1993 Oct 1; 82: 1949–53

    PubMed  CAS  Google Scholar 

  84. Lazzarino M, Corso A, Regazzi MB, et al. Modulation of all-trans retinoic acid pharmacokinetics in acute promyelocytic leukaemia by prolonged interferon-α therapy. Br J Haematol 1995; 90: 928–30.

    PubMed  CAS  Google Scholar 

  85. Hoffmann-La Roche Ltd. Vesanoid (tretinoin) product monograph. Basel, Switzerland, 1994.

  86. Adamson PC, Balis FM, Smith MA, et al. Dose-dependent pharmacokinetics of all-trans-retinoic acid. J Natl Cancer Inst 1992 Sep 2; 84: 1332–5.

    PubMed  CAS  Google Scholar 

  87. Adamson PC. Pharmacokinetics of all-trans-retinoic acid: clinical implications in acute promyelocytic leukemia. Semin Hematol 1994 Oct; 31 Suppl. 5: 14–7

    PubMed  CAS  Google Scholar 

  88. Avvisati G, Petti MC, Mandelli F. What is the best treatment for acute promyelocytic leukemia? Leuk Lymphoma 1993 Nov; 11 Suppl. 2: 29–35

    PubMed  Google Scholar 

  89. Fenaux P. Management of acute promyelocytic leukemia. Eur J Haematol 1993 Feb; 50: 65–73.

    Google Scholar 

  90. Dombret H, Castaigne S, Fenaux P, et al. Induction treatment of acute promyelocytic leukemia using all-trans retinoic acid. Controversies about dosage, advantages and side-effect management. Leukemia 1994; 8 Suppl. 3: S73–5.

    PubMed  Google Scholar 

  91. Castaigne S, Lefebvre P, Chomienne C, et al. Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia. Blood 1993 Dec 15; 82: 3560–3.

    PubMed  CAS  Google Scholar 

  92. Huang ME, Ye Y-C, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988 Aug; 72: 567–72.

    Google Scholar 

  93. Avvisati G, Baccarani M, Ferrara F, et al. AIDA protocol (all-trans retinoic acid + idarubicin) in the treatment of newly diagnosed acute promyelocytic leukemia (APL): a pilot study of the Italian Cooperative Group Gimema [abstract 1505]. Blood 1994; 84 Suppl. Nov: 380a.

    Google Scholar 

  94. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukaemia. I. Clinical results. Blood 1990 Nov 1; 76: 1704–9.

    PubMed  CAS  Google Scholar 

  95. Degos L, Chomienne C, Daniel MT, et al. Treatment of first relapse in acute promyelocytic leukaemia with all-trans retinoic acid [letter]. Lancet 1990 Dec 8; 336: 1440–1.

    PubMed  CAS  Google Scholar 

  96. Kanamaru A, Takemoto Y, Tanimoto M, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Blood 1995 March 1; 85: 1202–6.

    PubMed  CAS  Google Scholar 

  97. Ohno R, Ohnishi K, Takeshita A, et al. All-trans retinoic acid therapy in relapsed/refractory or newly diagnosed acute promyelocytic leukemia (APL) in japan. Leukemia 1994; 8 Suppl. 3: S64–9.

    PubMed  Google Scholar 

  98. Wiley JS, Firken FC, for the Australian Leukaemia Study Group. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia 1995: 774–8

  99. Eardley AM, Heller G, Warrell JRP. Morbidity and costs of remission induction therapy with all-trans retinoic acid compared with standard chemotherapy in acute promyelocytic leukemia. Leukemia 1994 Jun; 8: 934–9.

    Google Scholar 

  100. Fenaux P, Wattel E, Archimbaud E, et al. Prolonged follow-up confirms that all-trans retinoic acid followed by chemotherapy reduces the risk of relapse in newly diagnosed acute promyelocytic leukemia. Blood 1994 Jul 15; 84: 666–7.

    PubMed  CAS  Google Scholar 

  101. Takeshita A, Sakamaki H, Miyawaki S, et al. Significant reduction of medical costs by differentiation therapy with all-trans retinoic acid during remission induction of newly diagnosed patients with acute promyelocytic leukemia. Cancer 1995; 76: 602–8.

    PubMed  CAS  Google Scholar 

  102. Fenaux P, Chastang C, Chomienne C, et al. Tretinoin with chemotherapy in newly diagnosed acute promyelocytic leukaemia. Lancet 1994 Apr 23; 343: 1033.

    PubMed  CAS  Google Scholar 

  103. Degos L, Dombret H, Chomienne C, et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia? Blood 1995 May 15; 85 (10): 2643–53.

    PubMed  CAS  Google Scholar 

  104. Tallman MS, Rowe JM. Acute promyelocytic leukemia: a paradigm for differentiation therapy with retinoic acid. Blood Rev 1994 Jun; 8: 70–8.

    Google Scholar 

  105. Fenaux P, Chastang C, Chomienne C, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all trans-retinoic acid (ATRA) combined with chemotherapy: the European experience. Leuk Lymphoma 1995 Feb; 16: 431–7.

    Google Scholar 

  106. Seiter K, Miller WH, Feldman EJ, et al. Pilot study of all-trans retinoic acid as post-remission therapy in patients with acute promyelocytic leukemia. Leukemia 1995; 9: 15–8.

    PubMed  CAS  Google Scholar 

  107. Degos L, Castaigne S, Fenaux P, et al. All trans retinoic acid in acute promyelocytic leukemia. Nouv Rev Fr Hematol 1991; 33: 183–5.

    PubMed  CAS  Google Scholar 

  108. Mahmud N, Tsukada T, Taniguchi M, et al. Successful continuous treatment with all-trans retinoic acid for acute promyelocytic leukemia; secondary malignancy after the treatment of osteosarcoma. Intern Med 1994 Oct; 33: 654–7.

    Google Scholar 

  109. Liang R, Chow WS, Chiu E, et al. Effective salvage therapy using all-trans retinoic acid for relapsed and resistant acute promyelocytic leukemia. Anticancer Drugs 1993 Jun; 4: 339–40.

    Google Scholar 

  110. Bashford J, Szer J, Wiley JS, et al. Treatment of acute promyelocytic leukaemia relapsing after allogeneic bone marrow transplantation with all-trans-retinoic acid: suppression of the leukaemic clone. Br J Haematol 1991 Oct; 79: 331–4.

    Google Scholar 

  111. Levine K, DeBlasio A, Miller WH. Molecular diagnosis and monitoring of acute promyelocytic leukemia treated with retinoic acid. Leukemia 1994 Apr; 8 Suppl. 1: 116–20

    Google Scholar 

  112. Miller Jr WH, Dmitrovsky E. Retinoic acid and its rearranged receptor in the treatment of acute promyelocytic leukemia. Important Adv Oncol 1993: 81–90

  113. LoCoco F, Pelicci PG, Biondi A. Clinical relevance of the PML/RAR-a gene rearrangement in acute promyelocytic leukaemia. Leuk Lymphoma 1994 Feb; 12: 327–32.

    Google Scholar 

  114. Borrow J, Solomon E. Molecular analysis of the t(15;17) trans-location in acute promyelocytic leukaemia. Baillieres Clin Haematol 1992 Oct; 5: 833–56.

    Google Scholar 

  115. Grignani F, Fagioli M, Ferrucci PF, et al. The molecular genetics of acute promyelocytic leukemia. Blood Rev 1993 Jun; 7: 87–93.

    Google Scholar 

  116. Laczika K, Mitterbauer G, Korninger L, et al. Rapid achievement of PML-RARα polymerase chain reaction (PCR)-negativity by combined treatment with all-trans-retinoic acid and chemotherapy in acute promyelocytic leukemia: a pilot study. Leukemia 1994 Jan; 8: 1–5.

    Google Scholar 

  117. Biondi A, Rambaldi A, Pandolfi PP, et al. Molecular monitoring of the myl/retinoic acid receptor-α fusion gene in acute promyelocytic leukemia by polymerase chain reaction. Blood 1992 Jul 15; 80: 492–7.

    PubMed  CAS  Google Scholar 

  118. Cornic M, Delva L, Guidez F, et al. Induction of retinoic acid-binding protein in normal and malignant human myeloid cells by retinoic acid in acute promyelocytic leukaemia patients. Cancer Res 1992 Jun 15; 52: 3329–34.

    PubMed  CAS  Google Scholar 

  119. Delva L, Cornic M, Balitrand N, et al. Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993 Oct 1; 82: 2175–81.

    PubMed  CAS  Google Scholar 

  120. Robertson KA, Emami B, Collins SJ. Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity. Blood 1992 Oct 15; 80: 1885–9.

    PubMed  CAS  Google Scholar 

  121. Li YP, Said F, Gallagher RE. Retinoic acid-resistant HL-60 cells exclusively contain mutant retinoic acid receptor-α. Blood 1994 Jun 1; 83: 3298–302.

    PubMed  CAS  Google Scholar 

  122. Tsurumi H, Tojo A, Takahashi T, et al. The combined effects of all-trans retinoic acid and granulocyte colony-stimulating factor as a differentiation induction therapy for acute promyelocytic leukemia. Intern Med 1993 Aug; 32: 648–50.

    Google Scholar 

  123. Nakajima K, Hatake K, Miyata T, et al. Acute promyelocytic leukaemia, tretinoin, and granulocyte colony-stimulating factor [letter]. Lancet 1994 Jan 15; 343: 173–4.

    PubMed  CAS  Google Scholar 

  124. Usuki K, Ikeda Y, Kitazume K, et al. Filgrastim combined with tretinoin in acute promyelocytic leukaemia. Lancet 1994 Mar 26; 343: 803–4.

    PubMed  CAS  Google Scholar 

  125. Koller E, Kreiger O, Kasparu H, et al. Restoration of all-trans retinoic acid sensitivity by interferon in acute promyelocytic leukaemia [letter]. Lancet 1991 Nov 2; 338: 1154–5.

    PubMed  CAS  Google Scholar 

  126. Warrell Jr RP. Retinoid resistance [letter]. Lancet 1993 Jan 9; 341: 126.

    PubMed  Google Scholar 

  127. Tallman MS, Hakimian D, Kwaan HC, et al. New insights into the pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 1993 Sep; 11: 27–36.

    Google Scholar 

  128. Frankel SR, Eardley A, Lauwers G, et al. The ‘retinoic acid syndrome’ in acute promyelcytic leukemia. Ann Intern Med 1992 Aug 15; 117: 292–6.

    PubMed  CAS  Google Scholar 

  129. Vahdat L, Maslak P, Miller Jr WH, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-α isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 1994 Dec 1; 84: 3843–9.

    PubMed  CAS  Google Scholar 

  130. Warrell Jr RP, Maslak P, Eardley A, et al. Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience. Leukemia 1994 Jun; 8: 929–33.

    Google Scholar 

  131. Frankel SR. Acute promyelocytic leukemia. New insights into diagnosis and therapy. Hematol Oncol Clin North Am 1993 Feb; 7: 109–38.

    Google Scholar 

  132. Cox NH, O’Brien HAW. Sweet’s syndrome associated with trans-retinoic acid treatment in acute promyelocytic leukaemia. Clin Exp Dermatol 1994 Jan; 19: 51–2.

    Google Scholar 

  133. Tomas JF, Escudero A, Fernandez-Ranada JM. All-trans retinoic acid treatment and Sweet syndrome [letter]. Leukemia 1994 Sep; 8: 1596.

    Google Scholar 

  134. Giralt S, O’Brien S, Weeks E, et al. Leukemia cutis in acute promyelocytic leukemia: report of three cases after treatment with all-trans retinoic acid. Leuk Lymphoma 1994 Aug; 14: 453–6.

    Google Scholar 

  135. Hakimian D, Tallman MS, Zugerman C, et al. Erythema nodosum associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Leukemia 1993 May; 7: 758–9.

    Google Scholar 

  136. Toh CH, Winfield DA. All-trans retinoic acid and side-effects [letter]. Lancet 1992 May 16; 339: 1239–40.

    PubMed  CAS  Google Scholar 

  137. Nagasawa M, Okawa H. All-trans retinoic acid induced hypercalcemia in a patient with acute promyelocytic leukemia: its relation to increased PTH-rP [letter]. Int J Hematol 1994 Feb; 59: 143–4.

    Google Scholar 

  138. Sakakibara M, Ichikawa M, Amano Y, et al. Hypercalcemia associated with all-trans-retinoic acid in the treatment of acute promyelocytic leukemia. Leuk Res 1993 May; 17: 441–3.

    Google Scholar 

  139. Akiyama H, Nakamura N, Nagasaka S, et al. Hypercalcaemia due to all-trans retinoic acid [letter]. Lancet 1992 Feb 1; 339: 308–9.

    PubMed  CAS  Google Scholar 

  140. Suzumiya J, Asahara F, Katakami H, et al. Hypercalcaemia caused by all-trans retinoic acid treatment of acute promyelocytic leukaemia: case report. Eur J Haematol 1994 Aug; 53: 126–7.

    Google Scholar 

  141. Izumi T, Hatake K, Miura Y Acute promyelocytic leukemia [letter]. N Engl J Med 1994 Jan 13; 330: 141

    PubMed  CAS  Google Scholar 

  142. Patterson WK, Sage RE, Keefe DM. Haemorrhagic gastritis in two patients treated with all-trans-retinoic acid in acute promyelocytic leukaemia. Aust N Z J Med 1994 Jun; 24: 314–5.

    Google Scholar 

  143. Koike T, Tatewaki W, Aoki A, et al. Brief report: severe symptoms of hyperhistaminemia after the treatment of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid) [see comments]. N Engl J Med 1992 Aug 6; 327: 385–7.

    PubMed  CAS  Google Scholar 

  144. Rothmann F, Pasold R, Gerhardt A, et al. Aseptic perimyocarditis: a rare event of retinoic acid syndrome. A case report. Br J Haematol 1994; 87 Suppl. 1: 19.

    Google Scholar 

  145. Miranda N, Oliveira P, Frade MJ, et al. Myositis with tretinoin [letter]. Lancet 1994 Oct 15; 344: 1096.

    PubMed  CAS  Google Scholar 

  146. Shibata K, Shimamoto Y, Ishibashi S, et al. Life-threatening hepatic toxicity caused by all-trans-retinoic acid in a patient with acute promyelocytic leukaemia. Clin Lab Haematol 1994 Jun; 16: 191–5.

    Google Scholar 

  147. Lopez P, Hayne O. Case report — all-trans-retinoic acid, hyperleukocytosis, and marrow infarction. Am J Hematol 1992 Dec; 41: 305–6.

    Google Scholar 

  148. Dreosti LM, Bezwoda W, Gunter K. Bone marrow necrosis following all-trans retinoic acid therapy for acute promyelocytic leukaemia. Leuk Lymphoma 1994 Apr; 13: 353–6.

    Google Scholar 

  149. Limentani SA, Pretell JO, Potter D, et al. Bone marrow necrosis in two patients with acute promyelocytic leukemia during treatment with all-trans retinoic acid. Am J Hematol 1994 Sep; 47: 50–5.

    Google Scholar 

  150. Abu-el-Asrar AM, al-Momen AK, Harakati MS. Terson’s syndrome in a patient with acute promyelocytic leukemia on all-trans retinoic acid treatment. Doc Ophthalmol 1993; 84: 373–8.

    PubMed  CAS  Google Scholar 

  151. Shikoshi K, Takada M, Nakatani N, et al. Acute promyelocytic leukemia complicated by frequent seizures during treatment with all-trans retinoic acid [in Japanese]? Gann no Rinsho 1994; 40 (10): 1086–90.

    Google Scholar 

  152. de-Lacerda JF, do-Carmo JA, Guerra ML, et al. Multiple thrombosis in acute promyelocytic leukaemia after tretinoin [letter]. Lancet 1993 Jul 10; 342: 114–5.

    PubMed  CAS  Google Scholar 

  153. Runde V, Aul C, Heyll A. All-trans retinoic acid — not only a differentiating agent, but also an inducer of thromboembolic events in patients with acute promyelocytic leukemia [abstract]. Onkologie 1991 Oct; 14 Suppl. 2: 134

    Google Scholar 

  154. Ikeda Y, Yoshinaga K, Iki S, et al. Acute promyelocytic leukemia (APL) resulting in broad cerebral infarction during all-trans retinoic acid (ATRA) treatment [in Japanese]. Rinsho Ketsueki 1994 Feb; 35: 183–7.

    Google Scholar 

  155. Mahmoud HH, Hurwitz CA, Roberts WM, et al. Tretinoin toxicity in children with acute promyelocytic leukaemia. Lancet 1993 Dec 4; 342: 1394–5.

    PubMed  CAS  Google Scholar 

  156. de-Lacerda JF. Toxicity of tretinoin in acute promyelocytic leukaemia [letter]. Lancet 1994 Feb 5; 343: 360–1.

    PubMed  CAS  Google Scholar 

  157. Hwang WL, Gau JP, Chen MC, et al. Treatment of acute promyelocytic leukemia with all-trans retinoic acid -successful control of hyperleukocytosis and leukostasis syndrome with leukaphereses and hydroxyurea. Am J Hematol 1993 Aug; 43: 323–4.

    Google Scholar 

  158. Hashimoto S, Koike T, Tatewaki W, et al. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy for prophylaxis of hemorrhage. Leukemia 1994 Jul; 8: 1113–5.

    Google Scholar 

  159. Stentoft J, Nielsen JL, Hvidman LE. All-trans retinoic acid in acute promyelocytic leukemia in late pregnancy. Leukemia 1994 Sep; 8: 1585–8.

    Google Scholar 

  160. Harrison P, Chipping P, Fothergill GA. Successful use of all-trans retinoic acid in acute promyelocytic leukaemia presenting during the second trimester of pregnancy. Br J Haematol 1994 Mar; 86: 681–2.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Jane C. Gillis & Karen L. Goa

Authors
  1. Jane C. Gillis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen L. Goa
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Various sections of the manuscript reviewed by: G. Avvisati, Department of Human Biopathology, University ‘La Sapienza’, Rome, Italy; G. Bonadonna, Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; G. Brown, Department of Immunology, University of Birmingham, Birmingham, England; C. Chomienne, Laboratoire de Biologie Cellulaire Hématopoïétique, Université Paris, Paris, France; P. Fenaux, Service des Maladies du Sang, Centre Hospitalier Regional Universitaire de Lille, Lille, France; L. Glasser, Department of Pathology, Rhode Island Hospital, Providence, Rhode Island, USA; D. Grimwade, Somatic Cell Genetics, Imperial Cancer Research Fund Laboratories, London, England; R. Ohno, Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; W. Schroyens, Department of Haematology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium; J. Szer, Department of Clinical Haematology and Medical Oncology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia; I. Trayner, Department of Molecular Medicine, King’s School of Medicine and Dentistry, University of London, London, England; S. Waxman, Department of Medicine, The Mount Sinai Hospital, New York, New York, USA; X. Wu, Shanghai Medical Hospital, Shanghai, People’s Republic of China.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gillis, J.C., Goa, K.L. Tretinoin. Drugs 50, 897–923 (1995). https://doi.org/10.2165/00003495-199550050-00008

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199550050-00008

Keywords

  • Retinoic Acid
  • Reverse Transcription Polymerase Chain Reaction
  • Acute Promyelocytic Leukaemia
  • Tretinoin
  • Cytosine Arabinoside