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Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine.

Coyne CP, Jones T, Bear R - J Cancer Ther (2015)

Bottom Line: 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 chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, USA.

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 immunochemotherapeutics 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 immunochemotherapeutics, 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 immunochemotherapeutics.

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 chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine.

No MeSH data available.


Related in: MedlinePlus

Molecular design and chemical structure of the covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-HER2/neu] and gemcitabine-(C4-amide)-[anti-EGFR] synthesized utilizing a 2-stage organic chemistry reaction scheme that initially generates a gemcitabine UV-photoactivated intermediate. A synthetic covalent bond formed at the C4 cytosine-like mononamine group of gemcitabine chemotherapeutic and the side chains of amino acid residues within the sequence of immunoglobulin fractions.
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Figure 1: Molecular design and chemical structure of the covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-HER2/neu] and gemcitabine-(C4-amide)-[anti-EGFR] synthesized utilizing a 2-stage organic chemistry reaction scheme that initially generates a gemcitabine UV-photoactivated intermediate. A synthetic covalent bond formed at the C4 cytosine-like mononamine group of gemcitabine chemotherapeutic and the side chains of amino acid residues within the sequence of immunoglobulin fractions.

Mentions: The cytosine-like C4-monoamine of gemcitabine (0.738 mg, 2.80 × 10−3 mmoles) was reacted at a 2.5:1 molar-ratio with the amine-reactive N-hydroxysuccinimide ester “leaving” complex of succinimidyl 4,4-azipentanoate (0.252 mg, 1.12 × 10−3 mmoles) in the presence of triethylamine (TEA: 50 mM final concentration) utilizing dimethylsulfoxide as an anhydrous organic solvent system (Figure 1) [18] [19]. The reaction mixture formulated from stock solutions of gemcitabine and succinimidyl 4,4-azipentanoate was continually stirred gently at 25°C over a 4-hour incubation period in the dark and protected from exposure to light. The relatively long incubation period of 4 hours was utilized to maximize degradation of the ester group of any residual succinimidyl 4,4-azipentanoate that may not of reacted during the first 30 to 60 minutes with the C4 cytadine-like monoamine group of gemcitabine.


Simultaneous Dual Selective Targeted Delivery of Two Covalent Gemcitabine Immunochemotherapeutics and Complementary Anti-Neoplastic Potency of [Se]-Methylselenocysteine.

Coyne CP, Jones T, Bear R - J Cancer Ther (2015)

Molecular design and chemical structure of the covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-HER2/neu] and gemcitabine-(C4-amide)-[anti-EGFR] synthesized utilizing a 2-stage organic chemistry reaction scheme that initially generates a gemcitabine UV-photoactivated intermediate. A synthetic covalent bond formed at the C4 cytosine-like mononamine group of gemcitabine chemotherapeutic and the side chains of amino acid residues within the sequence of immunoglobulin fractions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376018&req=5

Figure 1: Molecular design and chemical structure of the covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-HER2/neu] and gemcitabine-(C4-amide)-[anti-EGFR] synthesized utilizing a 2-stage organic chemistry reaction scheme that initially generates a gemcitabine UV-photoactivated intermediate. A synthetic covalent bond formed at the C4 cytosine-like mononamine group of gemcitabine chemotherapeutic and the side chains of amino acid residues within the sequence of immunoglobulin fractions.
Mentions: The cytosine-like C4-monoamine of gemcitabine (0.738 mg, 2.80 × 10−3 mmoles) was reacted at a 2.5:1 molar-ratio with the amine-reactive N-hydroxysuccinimide ester “leaving” complex of succinimidyl 4,4-azipentanoate (0.252 mg, 1.12 × 10−3 mmoles) in the presence of triethylamine (TEA: 50 mM final concentration) utilizing dimethylsulfoxide as an anhydrous organic solvent system (Figure 1) [18] [19]. The reaction mixture formulated from stock solutions of gemcitabine and succinimidyl 4,4-azipentanoate was continually stirred gently at 25°C over a 4-hour incubation period in the dark and protected from exposure to light. The relatively long incubation period of 4 hours was utilized to maximize degradation of the ester group of any residual succinimidyl 4,4-azipentanoate that may not of reacted during the first 30 to 60 minutes with the C4 cytadine-like monoamine group of gemcitabine.

Bottom Line: 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 chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, USA.

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 immunochemotherapeutics 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 immunochemotherapeutics, 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 immunochemotherapeutics.

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 chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine.

No MeSH data available.


Related in: MedlinePlus