Date of Award

2021

Document Type

Thesis

Degree Name

MS in Pharmaceutical Science

Department

Pharmaceutical Sciences

First Advisor

Blase C. Billack

Second Advisor

Francis A.X. Schanne

Third Advisor

Sandra E. Reznik

Abstract

Mechlorethamine (HN2) is a type of nitrogen mustard alkylating agent that has been widely applied as an anticancer drug. HN2 is an analog of the corrosive reagent sulfur mustard, which is highly reactive with skin and organisms exposed to HN2 develop significant skin irritation, edema, erythema, and disruption of the dermal-epidermal junction (DEJ). These pathological affects lead to tissue damage, activate wound repair mechanisms and, if unresolved, result in necrosis. The purpose of the present study was to evaluate the time-dependent effects of HN2 on the expression of three different proteins using immunohistochemistry (IHC) and previously prepared and preserved formalin-fixed paraffin embedded mouse ear tissues. The timecourse included IHC of tissue samples harvested at 1 hr, 2 hr, 4 hr, 8 hr and 24 hr after topical exposure to HN2. The marker proteins investigated here included p53 binding protein (53BP1), inducible nitric oxide synthase (iNOS) and Collagen-XVII (COL-17). HN2 was found to significantly inhibit the expression of all three proteins in a time-dependent manner. With regard to 53BP1, HN2 exposure led to decreased tissue expression at 2 hr, 4 hr and 8 hr following treatment. iNOS expression was reduced by HN2 at all time points examined. COL-17 was reduced in a linear fashion at time points ≥ 2 hr. The results from this study provided new information regarding the roles of 53BP1, iNOS and COL-17 in the toxicological mechanisms of cutaneous injury induced by nitrogen mustard.

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