MDI 301 suppresses myeloid leukemia cell growth in vitro and in vivo without the toxicity associated with all-trans retinoic acid therapy

Abstract

MDI 301 is a novel 9-cis retinoic acid derivative in which the terminal carboxylic acid group has been replaced by a picolinate ester. MDI 301, a retinoic acid receptor-α - agonist, suppressed the growth of several human myeloid leukemia cell lines (HL60, NB4, OCI-M2, and K562) in vitro and induced cell-substrate adhesion in conjunction with upregulation of CD11b. Tumor growth in HL60-injected athymic nude mice was reduced. In vitro, MDI 301 was comparable to all-trans retinoic acid (ATRA) whereas in vivo, MDI 301 was slightly more efficacious than ATRA. Most importantly, unlike what was found with ATRA treatment, MDI 301 did not induce a cytokine response in the treated animals and the severe inflammatory changes and systemic toxicity seen with ATRA did not occur. A retinoid with these characteristics might be valuable in the treatment of promyelocytic leukemia, or, perhaps, other forms of myeloid leukemia.

ATRA treatment slowed P-selectin-mediated rolling of flowing HL60 cells in a mechano-chemical-dependent manner

“…ATRA has been widely applied to APL therapy despite the fact that DS, a severe APL complication, is relatively common in APL patients undergoing induction therapy with ATRA ( 19 ). In examining morphologies, adhesive molecule expression, and growth curve, ATRA dose and stimulus time are key mediators for differentiating HL60 cells ( Figures 1 , 2 ), which is consistent with previous works ( 5 , 9 , 22 ). Based on a balance of agent toxicity and cell function recovery, 1 × 10 -6 M dose and 120 h of stimulus time of ATRA have been picked herein as the optimal conditions at which the differentiated HL60 cells are neutrophil-like ( Figures 1 , 2 ).…”

“…A dominant therapeutic strategy for leukemia is based on agent-induced differentiation of the abnormal cells (3,4). Various agents, such as phorbol esters, phospholipid scramblase 1, hyaluronan ester, dimethyl sulfoxide (DMSO), carotenoids (from crocus sativus), sesquitorpene lactones, and retinoic acid, can induce the differentiation of acute promyelocytic leukemia (APL) into functional and morphological mature granulocytes (5)(6)(7)(8)(9)(10)(11). All-trans retinoic acid (ATRA) is the first drug successfully used in leukemia therapy, and it results in up to 90% complete remission by specifically inducing the development of APL cells into mature myeloid cells instead of killing them (5,12).…”