Date of Award

2013

Document Type

Honors Thesis (Open Access)

Department

Colby College. Biology Dept.

Advisor(s)

Julie T. Millard

Second Advisor

Paul G. Greenwood

Third Advisor

Ethan A. Kohn

Abstract

Mechlorethamine (HN2), a nitrogen derivative of mustard gas, was the first synthetic anti-tumor chemotherapeutic because it forms covalent cross-links between strands of duplex DNA. HN2 represents a class of bifunctional alkylating agents that are both chemotherapeutic and carcinogenic: diepoxybutane (DEB), the active form of the pro-drug treosulfan, and epichlorohydrin (ECH), a structural hybrid of HN2 and DEB, also form covalent cross-links between DNA. While HN2 and DEB are clinically used as anti-tumor chemotherapeutics, ECH is a structural hybrid of these two compounds not used in a clinical setting. Accordingly, we aimed to understand the relationship between the cross-linking potential of these compounds and their ability to induce cell death (apoptosis). Cytotoxicity rankings were determined by assessing the median lethal dose (LD50) concentrations using MTT Cell Proliferation Assays for 12- and 24-h treatments (HN2 >> DEB > ECH; DEB > HN2 > ECH, respectively). Cross-linking potentials at equimolar concentrations suggest DEB > ECH > HN2 for a 24-h treatment. Finally, these compounds’ abilities to induce apoptosis at 12- and 24-h equitoxic concentrations were assayed over 12- and 24-h treatments, suggesting that DEB >> ECH > HN2. Accordingly, we propose a relationship between a compound’s ability to form cross-links and the induction of cell death and apoptosis (DEB > ECH > HN2) when considering reactivity and stability of unreacted cross-linkers over time. Future studies will aim to elucidate the cross-linking potential at equitoxic concentrations for each of these three compounds over multiple time frames.

Keywords

cancer treatment, chemotherapy, cell biology

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