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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

Relative anti-neoplastic cytotoxicity of individual and dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics against chemotherapeutic-resistant human mammary adenocarcinoma. Legends: (◆) gemcitabine-(C4-amide)-[anti-EGFR]; (▲) gemcitabine-(C4-amide)-[anti-HER2/neu]; and (■) gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu]. Individual or dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics formulated at gradient 50/50 gemcitabine-equivalent concentrations were incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.
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Figure 8: Relative anti-neoplastic cytotoxicity of individual and dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics against chemotherapeutic-resistant human mammary adenocarcinoma. Legends: (◆) gemcitabine-(C4-amide)-[anti-EGFR]; (▲) gemcitabine-(C4-amide)-[anti-HER2/neu]; and (■) gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu]. Individual or dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics formulated at gradient 50/50 gemcitabine-equivalent concentrations were incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.

Mentions: The dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] evaluated as a gemcitabine-standardized 50/50 molar equivalent formulation in addition to gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] all produced progressive increases in anti-neoplastic cytotoxicity against chemotherapeutic resistant mammary adenocarcinoma (SKBr-3) as a function of increases in gemcitabine-equivalent concentration at and between 10−10 M and 10−6 M (Figure 8). Anti-neoplastic cytotoxicity of gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] was 24.3%, 24.5%, 32.8%, 69.9%. and 83.7% (75.7%, 75.5%, 67.2%, 30.1% and 16.3% residual survival) at the gemcitabine-equivalent concentrations of 10−10 M, 10−9 M, 10−8 M, 10−7 M and 10−6 M respectively (Figure 8). Gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity that were less than for gemcitabine-(C4-amide)-[anti-EGFR] but consistently greater than levels for gemcitabine-(C4-amide)-[anti-HER2/neu] at and between the gemcitabine-equivalent concentrations of 10−10 M and 10−6 M respectively (Figure 8). Anti-neoplastic cytotoxicity for gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] compared to gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] reached maximum or near maximum levels of 83.7%, 99.6%, and 30.8% (16.3%, 0.4%, and 69.2% residual survival) respectively (Figure 8).


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)

Relative anti-neoplastic cytotoxicity of individual and dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics against chemotherapeutic-resistant human mammary adenocarcinoma. Legends: (◆) gemcitabine-(C4-amide)-[anti-EGFR]; (▲) gemcitabine-(C4-amide)-[anti-HER2/neu]; and (■) gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu]. Individual or dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics formulated at gradient 50/50 gemcitabine-equivalent concentrations were incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Relative anti-neoplastic cytotoxicity of individual and dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics against chemotherapeutic-resistant human mammary adenocarcinoma. Legends: (◆) gemcitabine-(C4-amide)-[anti-EGFR]; (▲) gemcitabine-(C4-amide)-[anti-HER2/neu]; and (■) gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu]. Individual or dual simultaneous combinations of covalent gemcitabine immunochemotherapeutics formulated at gradient 50/50 gemcitabine-equivalent concentrations were incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.
Mentions: The dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] evaluated as a gemcitabine-standardized 50/50 molar equivalent formulation in addition to gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] all produced progressive increases in anti-neoplastic cytotoxicity against chemotherapeutic resistant mammary adenocarcinoma (SKBr-3) as a function of increases in gemcitabine-equivalent concentration at and between 10−10 M and 10−6 M (Figure 8). Anti-neoplastic cytotoxicity of gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] was 24.3%, 24.5%, 32.8%, 69.9%. and 83.7% (75.7%, 75.5%, 67.2%, 30.1% and 16.3% residual survival) at the gemcitabine-equivalent concentrations of 10−10 M, 10−9 M, 10−8 M, 10−7 M and 10−6 M respectively (Figure 8). Gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity that were less than for gemcitabine-(C4-amide)-[anti-EGFR] but consistently greater than levels for gemcitabine-(C4-amide)-[anti-HER2/neu] at and between the gemcitabine-equivalent concentrations of 10−10 M and 10−6 M respectively (Figure 8). Anti-neoplastic cytotoxicity for gemcitabine-(C4-amide)-[anti-EGFR] in dual simultaneous combination with gemcitabine-(C4-amide)-[anti-HER2/neu] compared to gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] reached maximum or near maximum levels of 83.7%, 99.6%, and 30.8% (16.3%, 0.4%, and 69.2% residual survival) respectively (Figure 8).

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