Kevin S. Fay

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

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.

Abstract 3890: The PhScN peptide as a highly potent inhibitor of basement membrane invasion in vitro and lung colonization in nude mice by metastatic human prostate cancer cells

Surgery and radiation can cure localized prostate cancer, but not metastatic disease. Our research has shown that activated Δ5α1 integrin fibronectin receptors mediate metastatic invasion by human prostate cancer cell lines, DU 145 and PC-3, as well as angiogenic invasion by human microvascular endothelial cells (hmvec). Thus, activated Δ5α1 receptors are key to metastatic progression. To inhibit metastatic invasion, we devised the Ac-PHSCN-NH2 peptide, PHSCN, licensed as ATN-161. Systemic ATN-161 monotherapy was well tolerated in Phase I trial, and halted metastatic progression for 4-14 months in 35% of patients; however, it was not potent enough for easy administration. Thus, there are some major difficulties with ATN-161 as a drug. Also, PHSCN can be degraded by endoproteinases, enzymes that cleave between its linked L-amino acids. Since tumors secrete abundant endoproteinases, we devised a potent, exo- and endoproteinase-resistant, Δ5α1αtargeted invasion inhibitor, the Ac-PhScN-NH2 peptide (PhScN). Because it contains mirror image D-isomers of His (h) and Cys (c) separating L-isomers of Pro, Ser, and Asn, is resistant to endoproteolytic degradation. Our results suggest that PhScN is 27,000 to 340,000-fold more potent than PHSCN at blocking Δ5α1-mediated, serum-induced, or serum-free PHSRN peptide-induced invasion in vitro by metastatic human DU 145 and PC-3 prostate cancer cells. Our results also indicate that a single pretreatment of suspended DU 145 and PC-3 cells with varying concentrations of the PhScN peptide prior to intravenous injection reduces lung colony formation in athymic, nude mice by 100,000 to 300,000-fold, relative to lung metastasis inhibition by the parental PHSCN peptide. Because Δ5α1 integrin also supports survival, we determined the effects of elevated PhScN concentrations on clonogenic DU 145 and PC-3 survival in vitro. We found that PhScN has no appreciable effect on clonogenic survival, suggesting that its potent anti-metastatic activity is due to invasion inhibition in lung microvasculature. Consistent with this hypothesis, our preliminary results suggest that PhScN pretreatment is also significantly more potent method for preventing extravasation into lung tissue than pretreatment with the parental PHSCN peptide. Since our published results show that the PHSCN polylysine dendrimer (PHSCNGGK-MAP) is 100-fold more potent than the PHSCN peptide at inhibiting DU 145 and PC-3 lung colonization, the results presented here suggest that D-amino acid substitution in the PHSCN sequence, thereby forming the PhScN peptide or dendrimer (PhScNGGK-MAP) may be an excellent strategy for the synthesis of highly potent Δ5α1-targeted inhibitors of metastatic invasion and lung colonization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3890. doi:1538-7445.AM2012-3890