Promyelocytic leukemia, retinoids

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. 

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. 

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],... 

An increased risk of thrombotic events, especially coronary thrombosis, has been reported in elderly patients taking retinoids (33). Two patients with acute promyelocytic leukemia developed thrombus in the right ventricle during induction treatment with tretinoin plus idarubicin (34). 

Acute febrile neutrophilic dermatosis (Sweet s syndrome) can occur in patients with acute promyelocytic leukemia given a retinoid. Sweet s syndrome is characterized by five cardinal features fever, neutrophilia, multiple raised painful asymmetric erythematous cutaneous plaques, dermal infiltrates consisting of mature neutrophils, and a rapid response to glucocorticoid therapy. In up to 10-20% of cases it precedes or coincides with a diagnosis of malignancy, most commonly acute myelogenous leukemia. In cases associated with tretinoin the symptoms come on at 7-34 days and the skin lesions are seen on the face, limbs, and back. 

There is now compelling evidence from the number of retinoids in the clinic and in clinical studies (Table 12.1) that these molecules exhibit efficacy in human diseases. The use of ATRA for the treatment of acute promyelocytic leukemia is considered a successful therapy in our view. It is the hope that the application of retinoids, most probably more receptor specific retinoids/rexinoids, in combination with other chemotherapeutic agents, will lead to broad clinical utility in many diseases. We anticipate that the retinoid field will continue to expand as researchers gain more information about new levels of retinoid/rexinoid biology and their relevance to human diseases. 

Tretinoin is a retinoid, which decreases cohesiveness and stimulates mitotic activity and turnover of follicular epithelial cells, resulting in decreased formation and increased extrusion of comedones. PO induces maturation of acute promyelocytic leukemia cells followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete... 

Retinoid receptor RARa Translocation Nucleus Acute promyelocytic leukemia... 

In HL60 (promyelocytic leukemia cell fine), RAR and RXR binding also stimulates apoptosis (Bollag and Holdener, 1992) the same occurs in medulloblastoma cell fines, at least partially, through caspase-3 activation (Gumireddy et ai, 2003). Similarly, CD437, a synthetic retinoid, induces the initial stages of apoptosis in human respiratory cells via a mitochondrial pathway independent... 

In addition to growth inhibition and apoptosis, retinoids are well-established as redifferentiating agents in vitro. Redifferentiation and growth inhibition have been documented in osteosarcoma cell lines in vitro (Barroga et al, 1999). In human myeloid leukemia cell lines, all-tra wr-RA can induce differentiation to granulocytic- or monocytic-like cells. The same effect can be demonstrated in leukemic cells from patients with promyelocytic leukemia (Chomienne ij /., 1990). 

There is evidence that the effects of retinoids observed in vitro can be translated into chnical responses in promyelocytic leukemia and neuroblastoma, although the responses in many solid tumors have been disappointing (Frankel et al., 1994 Matthay et al., 1999 Freemantle et al., 2003). In thyroid carcinoma, a fimited number of human studies have been performed to investigate the effects of retinoids on 1-131 uptake (summarized in Table 102.1). 

Promotion of cellular differentiation is a promising postulated mechanism for chemoprevention. Several compounds have been reported to induce cell differentiation, including retinoids, vitamin D3, and genistein. " Resveratrol is capable of inducting differentiation in some hematological malignant cell lines, colon cancers, and neuroblastoma. Jang et al. reported that incubation of the promyelocytic leukemia HL-60 cells with resveratrol induces cell differentiation and reduction of DNA synthesis. 

Hashimoto, Y., Kagechika, H, Kawachi, E., and Shudo, K. (1988) Specific uptake of retinoids into human promyelocytic leukemia cells HL-60 by retinoid-specific binding protein Possibly the true retinoid receptor Jpn J Cancer Res 79, 473-484. 

Chomienne, C., Fenaux, P., and Degos, L. (1996) Retinoid differentiation therapy in promyelocytic leukemia, FASEB J. 10, 1025-1030. 

Pandolfi, P. P., Grignam, F., Alcalay, M, Mencarelli, A, Biondi, A, Lo Coco, F, Grignani, F., and Pelicci, P G. (1991) Structure and origin of the acute promyelocytic leukemia myl/RARa cDNA and characterization of its retinoid-binding and transactivation properties Oncogene 6,1285-1292... 

To the extent that it is possible, we attempt to simplify the picture by discussing separately each of the cellular systems in which evidence exists for retinoid-mediated effects on protein kinases and protein phosphorylation. In studies of the biochemical effects of retinoids we are again faced with the central role occupied by their specific effects on neoplastic cells. The cellular systems employed for these studies have been either murine embryonal carcinoma cells (F9) or human promyelocytic leukemia cells (HL-60), each of which has been demonstrated to undergo terminal differentiation to nonneoplastic cell types following retinoid treatment (see Section IV,B,1 and 2), or murine melanoma cells in which retinoids have a marked antiproliferative effect (Section IV,B,3). 

Indeed, it has even been shown that there are some fully neoplastic, transformed cells that can be induced to undergo terminal differentiation in response to treatment with retinoids, with loss of their neoplastic properties. The most striking examples of this phenomenon are the induction of terminal differentiation in murine F9 teratocarcinoma cells (Strickland and Mahdavi, 1978 Strickland, 1981) and human promyelocytic leukemia cells (Breitman et at., 1980, 1981, 1983). However, this does not appear to be a general effect of retinoids, and there are unfortunately only a limited number of instances in which such profound effects of retinoids on differentiation of invasive tumor cells have been shown. 

Takeshita A, Shibata Y, Shinjo K, Yanagi M, Tobita T, Ohnishi K, Miyawaki S, Shudo K, Ohno R (1996) Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid, Am80. Ann Int Med 124 893-896... 

Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiroka A, Karasuno T, Takeuchi M, Miyawaki S, Ueda R et al (1997) Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-tra 5-retinoic acid. Blood 90 967-973... 

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