Leukemia, acute promyelocytic

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Mologni L., Marches E., Nielsen P.E., Gai4BACOrti-Passerini C. Inhibition of promyelocytic leukemia (PML)/retinoic acid receptor-alpha and PML expression in acute promyelocytic leukemia cells by anti-PML peptide nucleic acid. Cancer Res. 2001 61 5468-5473. 

Dunphy CH, Polski JM, Johns G, et al. Acute promyelocytic leukemia, hypo-granular variant, with uncharacteristic staining with chloroacetate esterase. Leak. Lymphoma 2001 42 215-219. 

Granulocyte differentiation acute promyelocytic leukemia PBMCs (in vivo) Cultured bone marrow mononuclear cells (in vitro) All-trans retinoic acid (ATRA) Promoter analysis of ATRA response genes suggest molecular mechanism underlying ATRA-induced granulocytic differentiation [30]... 

Kwon SH, Ahn SH, Kim YK, Bae GU, Yoon JW, Hong S, Lee HY, Lee YW, Lee HW, Han JW. (2002) Apicidin, a histone deacetylase inhibitor, induces apoptosis and Fas/Fas ligand expression in human acute promyelocytic leukemia cells. J Biol Chem 111 2073-2080. 

Lu D-P, Qiu J-Y, Jiang B, Wang Q, Liu K-Y, Liu Y-R et al. Tetra-arsenic tetra-sulflde for the treatment of acute promyelocytic leukemia a pilot report. Blood 2002 99 3136-43. 

Mechanism of Action A retinoid that decreases cohesiveness of follicular epithelial cells. Increases turnover of follicular epithelial cells. Bacterial skin counts are not altered. Transdermal Exerts its effects on growth and differentiation of epithelial cells. Antineoplastic Induces maturation, decreases proliferation of acute promyelocytic leukemia (APL) cells. Therapeutic Effect Causes expulsion of blackheads alleviates fine wrinkles, hyperpigmentation causes repopulation of bone marrow and blood by normal hematopoietic cells. 

Other organoarsenicals, most notably lewisite (dichloro[2-chlorovinyl]arsine), were developed in the early twentieth century as chemical warfare agents. Arsenic trioxide was reintroduced into the United States Pharmacopeia in 2000 as an orphan drug for the treatment of relapsed acute promyelocytic leukemia and is finding expanded use in experimental cancer treatment protocols (see Chapter 54). Melarsoprol, another trivalent arsenical, is used in the treatment of advanced African trypanosomiasis (see Chapter 52). 

Retinoids also modulate gene expression acting and the post-transcriptional level. The P-carotene has also important implications from the clinical point of view. All E retinoic acid is used for patients with acute promyelocytic leukemia [1],... 

Lo-Coco F, Cimino G, Breccia M, Noguera NI, et al. 2004. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 104 1995-1999. 

A unique use of arsenic, in the form of arsenic trioxide (AS2O3), is for the treatment of cancer. Relapsed or refractory cases of acute promyelocytic leukemia have been successfully treated with this arsenical. Its use in the United States was approved by the US Food and Drug Administration (FDA) in 2000 (Antman, 2001). 

Acute promyelocytic leukemia A form of leukemia involving the infiltration of bone marrow by abnormal pre- and young leukocytes. 

Drug Arsenic trioxide (Trisenox] Primary Antineoplastic Indication(s) Acute promyelocytic leukemia Common Adverse Effects Dyspnea Gl distress (nausea, vomiting, diarrhea] headache fatigue others... 

Tretinoin (Vesanoid] Acute promyelocytic leukemia Cardiac arrhythmias edema blood pressure abnormalities (hypotension, hypertension] phlebitis respiratory tract problems muscle pain paresthesias CNS toxicity (depression, anxiety, confusion] skin rash Gl distress (abdominal distension nausea, vomiting]... 

Bastie JN, Balitrand N, Guillemot I, et al. Cooperative action of 1 alpha,25-dihydroxyvitamin D3 and retinoic acid in NB4 acute promyelocytic leukemia cell differentiation is transcriptionally controlled. Exp Cell Res. 2005 310 319-330. 

Acute promyelocytic leukemia Translocation PML/RARA PML/RARA All-frans retinoic acid, arsenic trioxide... 

Autoimmune deficiency disease Arylhydrocarbon hydroxylase receptor in humans and mice, respectively Acute promyelocytic leukemia All trans retinoic acid A member of the nuclear receptor family An inbred mouse strain An inbred mouse strain HIV receptor... 

A transcription factor implicated in acute promyelocytic leukemia A form of the retinoic acid receptor A member of the nuclear receptor family A member of the nuclear receptor family A form of the retinoic acid receptor Selective estrogen receptor modulators A channel locus associated with the Long QT syndrome... 

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