Author(s)

C. P. Coyne^1*, Toni Jones¹, Ryan Bear²

¹Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, USA.
¹Wise Center, Mississippi State University, Mississippi State, USA.

The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunoche-motherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition; prolong chemotherapeutic plasma half-life (reduces administration frequency); minimize innocent exposure of normal tissues and healthy organ systems; and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunoche-motherapeutics, gemcitabine-(C₄-amide)-[anti-EGFR] and gemcitabine-(C₄-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C₄-amide)-[anti-EGFR] and gemcitabine-(C₄-amide)-[anti-HER2/neu] between gemcitabine-equivalent concentrations of 10^-12 M and 10^-6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunoche-motherapeutics. Results: Gemcitabine-(C₄-amide)-[anti-EGFR], gemcitabine-(C₄-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C₄-amide)-[anti-EGFR] with gemcitabine-(C₄-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C₄-amide)-[anti-EGFR] and gemcitabine-(C₄-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10^-9 M and 10^-6 M. Dual simultaneous combinations of gemcitabine-(C₄-amide)-[anti-EGFR] with gemcitabine-(C₄-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C₄-amide)-[anti-EGFR] and gemcitabine-(C₄-amide)-[anti-HER2/neu] against chemothe-rapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-no-cysteine.

Gemcitabine, Anti-EGFR, Anti-HER2/neu, Covalent Immunochemotherapeutic, Gemcitabine-(C4-amide)-[Anti-EGFR], Gemcitabine-(C4-amide)-[Anti-HER2/neu], Mammary Adenocarcinoma (SKBr-3), [Se]-Methylselenocysteine

Coyne, C. , Jones, T. and Bear, R. (2015) Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine. Journal of Cancer Therapy, 6, 62-89. doi: 10.4236/jct.2015.61009.