Therapeutic Options in the Management of Acute Myelogenous Leukemia in Adults

Saez, Ruben A.

doi:10.1177/107327489700400502

Cited by 1 publication

(1 citation statement)

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“…Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang

Dawson²,

Ning³

et al. 2003

Blood

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IntroductionAcute myelogenous leukemia (AML) is a heterogeneous disease composed of numerous subclassifications displaying a wide spectrum of phenotypes. 1,2 The major therapeutic approach to this disease has been the use of chemotherapeutic agents with associated life-threatening toxicity. Although nonspecific in their effects, these regimens have significantly increased the survival of AML patients. [3][4][5] Recently, more targeted therapy has been developed. Treatment of acute promyelocytic leukemia (APL) patients with trans-retinoic acid (tRA) results in the differentiation of the leukemic cells, with 90% of the patients achieving a complete remission. [6][7][8] The tRA exerts its effect by modulating gene expression through its role as a ligand to the retinoic acid nuclear receptors, RARs, with the subsequent binding of this complex to the retinoic acid response element (RARE) consensus sequences located in the regulatory regions of retinoid-responsive genes. 9 The selective sensitivity of APL cells to tRA-mediated differentiation resides in their specific expression of a unique promyelocytic leukemia (PML)-RAR␣ fusion product that results in the subsequent maturation arrest of these cells at the promyelocyte stage [10][11][12] ; exposure of these cells to a micromolar concentration of tRA allows for the degradation of the PML-RAR␣ fusion product, with subsequent maturation of the APL cells. [13][14] Unfortunately, the other AML subtypes as classified by the French-American-British (FAB) classification demonstrate inherent resistance to tRA-mediated differentiation and induction of apoptosis. 15,16 We and others have recently described a novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN/CD437), which is a potent inducer of apoptosis in a variety of cell types and which displays resistance to tRA-mediated differentiation and apoptosis. [17][18][19][20][21] The mechanistic pathways by which AHPN induces apoptosis in malignant cells are not clearly defined. AHPN binds and transactivates both the RAR␤ and RAR␥ receptors. 22,23 The roles of these retinoid nuclear receptors in AHPN-mediated apoptosis are controversial. While some studies have suggested that binding and transactivation of RAR␥ are essential for AHPN/CD437-mediated apoptosis, 24,25 others have indicated that neither the RARs nor the retinoid X receptors (RXRs) to which AHPN does not bind or transactivate are involved. 20,21,26 bloodjournal.org FromIn the present study, we assessed the ability of the AHPN analog 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC/MM002) to induce apoptosis in a number of human AML cell lines as well as in primary cultures of leukemic blasts obtained from patients. The 3-Cl-AHPC differs from AHPN in its inability to recruit RAR coactivators and transactivate the RARs (Zhang et al 27 and data not shown). We found that 3-Cl-AHPC is a potent inducer of apoptosis in these cells, which display resistance to the antiproliferative/differentiating effects of tRA. The 3-C...

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Section: Introductionmentioning

confidence: 99%