alexa Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-HER2/neu] in Combination with Griseofulvin against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3)
ISSN: 2161-0444

Medicinal Chemistry
Open Access

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Research Article

Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-HER2/neu] in Combination with Griseofulvin against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3)

Coyne CP*, Toni Jones and Ryan Bear

Department of Basic Sciences, College of Veterinary Medicine at Wise Center, Mississippi State University, Mississippi State, Mississippi 39762, USA

*Corresponding Author:
Coyne CP
Department of Basic Sciences, College of Veterinary Medicine at Wise Center
Mississippi State University, Mississippi State, Mississippi 39762, USA
Tel: 662 325-1120
E-mail: [email protected]

Received date: April 20, 2013; Accepted date: June 27, 2013; Published date: June 29, 2013

Citation: Coyne CP, Jones T, Bear R (2013) Cytotoxic Anti-Neoplastic Potency of Gemcitabine-(C4-amide)-[anti-HER2/neu] in Combination with Griseofulvin against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3). Med chem 3:210-223. doi:10.4172/2161-0444.1000141

Copyright: © 2013 Coyne CP, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Introduction: Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeuticresistance and sequelae restrict gemcitabine utility in clinical oncology. Selective “targeted” gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure.

Methods: A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti-HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity of gemcitabine-(C4-amide)-[anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over-express the HER2/neu trophic membrane receptor. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-HER2/neu] and the tubulin/ microtubule inhibitor, griseofulvin was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin to evoke increased levels of cytotoxic anti-neoplatic potency compared to gemcitabine- (C4-amide)-[anti-HER2/neu].

Results: Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic and griseofulvin exerted cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with griseofulvin created increased levels of cytotoxic anti-neoplastic potency that were greater than was attainable with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone.

Conclusion: Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with griseofulvin can produce enhanced levels of cytotoxic anti-neoplastic activity and potentially provide a basis for treatment regimens with a wider marginof- safety. Such benefits would be possible through the collective properties of; [i] selective “targeted” gemcitabine delivery; [ii] relatively lower toxicity of griseofulvin compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti-cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide)-[anti-HER2/neu] compared to griseofulvin functioning as a tubulin/microtubule inhibitor.


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