TITLE:
Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine
AUTHORS:
C. P. Coyne, Toni Jones, Ryan Bear
KEYWORDS:
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
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.1,
January
16,
2015
ABSTRACT: 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] betweengemcitabine-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.