Differentiation, retinoid induced leukemia cells

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

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). 

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. 

Retinoid activities can also be modulated by the cellular retinoic acid-binding proteins (CRABPs) I and II. These proteins bind the natural retinoid trans-RA and potentiate its metabolic oxidation at the 4-position. ( )-4-[2-(3,5-Di-f-butylphenyl)propenyl]benzoic acid (CD55), which does not bind to CRABP and cannot be metabolized at its position corresponding to the 4-position of trans-RA, is far more potent than trans-RA in inducing the differentiation of HL-60 leukemia cells [43]. 

Hashimoto Y, Kagechika H, Kawachi E, Fukasawa H, Saito G, Shudo K (1996) Evaluation of differentiation-inducing activity of retinoids on human leukemia cell lines HL-60 and NB4. Biol Pharm Bull 19 1322-1328... 

Gianni M, Zanotta S, Terao M, Rambaldi A, Garattini E (1996) Interferons induce normal and aberrant retinoic-acid receptors type a in acute promyelocytic leukemia cells potentiation of the induction of retinoid-dependent differentiation markers. Int J Cancer 68 75-83... 

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. 

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. 

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