MDI 301, a non-irritating retinoid, induces changes in human skin that underlie repair

Abstract

Previous studies have demonstrated that all-trans retinoic acid (RA) increases collagen production and decreases matrix metalloproteinase (MMP) activity in organ-cultured human skin. Decreased MMP activity is associated with up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1). These changes are accompanied by a hyperplastic response in the epidermis. Here we show that a synthetic picolinic ester-substituted retinoid (designated as MDI 301) has comparable effects to those of RA in regard to these activities. What makes these findings of interest is that RA also stimulates elaboration of several pro-inflammatory cytokines and up-regulates leukocyte adhesion molecules in organ-cultured skin. MDI 301 does not induce such changes or is much less active. In a past study we showed that while RA was irritating to the skin of topically treated hairless mice, MDI 301 was essentially non-irritating under the same conditions [Varani et al. (2003) Arch. Dermatol Res 295:255-262]. Taken in conjunction with the findings from the past study, the present data suggest that MDI 301 will be similar to RA in capacity to repair damaged skin, but will be effective under conditions that are not irritating. These findings, thus, suggest that retinoid efficacy and clinically relevant irritancy are not inextricably linked. Potential for efficacy under conditions in which irritation is not observed is a strong rationale for further development of MDI 301 as a skin-repair agent.

MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin

“…29 In these regards, MDI 301 and RA are similar. With the synthetic retinoid, however, surrogate markers of inflammation that are up-regulated by RA in human skin organ culture are not increased.…”

“…In a recent study, this agent was shown to increase epidermal proliferation, decrease matrix metalloproteinase (MMP) activity and increase procollagen synthesis in organ-cultured human skin. 29 Unlike RA, MDI 301 did not induce expression of proinflammatory cytokines or lead to up-regulation of leukocyte adhesion molecules in the treated skin. When applied topically to the skin of hairless mice, essentially no skin irritation was observed.…”

“…With the synthetic retinoid, however, surrogate markers of inflammation that are up-regulated by RA in human skin organ culture are not increased. 29 Given this profile of activities, the use of MDI 301 in topical preparations should, in theory, have significant advantages over RA and other retinoids that are currently available as skin-repair agents. In the present study we demonstrate that MDI 301 does, in fact, have wound healing potential.…”

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

“…Studies carried out in rodents [30,31], Gottingen minipigs [32], and human skin organ culture [29,33] have shown that MDI 301 is similar to ATRA in terms of skin-repair efficacy, but induces much less skin irritation. In human skin organ culture, MDI 301 does not upregulate proinflammatory cytokines or alter adhesion factor expression, in contrast to what is observed with ATRA [28,29]. Given the lack of a proinflammatory response to MDI 301, the present study was carried out to compare MDI 301 with ATRA for effects on a series of human myeloid leukemia cell lines in vitro and in vivo.…”

“…Although mediators released from the tumor cells themselves are likely contributors to the syndrome, ATRA also affects host parenchymal elements including epithelial cells, fibroblasts, and endothelial cells. Release of proinflammatory cytokines from these cells in the skin has been shown to occur in response to ATRA treatment [28,29]. The skin irritation response in patients treated topically with ATRA (i.e.…”