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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 gemcitabine anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma over challenge (incubation) periods of different duration. Legends: (■) gemcitabine following a 96-hour incubation period; and (◆) gemcitabine following a 182-hour incubation period. Gemcitabine formulated at gradient gemcitabine-equivalent concentrations was incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of either 96-hours or 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.
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Figure 4: Relative gemcitabine anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma over challenge (incubation) periods of different duration. Legends: (■) gemcitabine following a 96-hour incubation period; and (◆) gemcitabine following a 182-hour incubation period. Gemcitabine formulated at gradient gemcitabine-equivalent concentrations was incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of either 96-hours or 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.

Mentions: Gemcitabine chemotherapeutic produced higher levels of anti-neoplastic cytotoxicity against chemotherapeutic resistant mammary adenocarcinoma during direct contact incubation periods of 182-hours compared to 96-hours especially at the gemcitabine-equivalent concentration of 10−6 M (Figure 4). Similarly, gemcitabine-(C4-amide)-[anti-EGFR] produced measurably higher levels of canti-neoplastic cytotoxicity when incubated with chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for direct contact periods of 182-hours compared to 96-hours (Figure 5 and Figure 6).


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 gemcitabine anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma over challenge (incubation) periods of different duration. Legends: (■) gemcitabine following a 96-hour incubation period; and (◆) gemcitabine following a 182-hour incubation period. Gemcitabine formulated at gradient gemcitabine-equivalent concentrations was incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of either 96-hours or 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 4: Relative gemcitabine anti-neoplastic cytotoxicity against chemotherapeutic-resistant mammary adenocarcinoma over challenge (incubation) periods of different duration. Legends: (■) gemcitabine following a 96-hour incubation period; and (◆) gemcitabine following a 182-hour incubation period. Gemcitabine formulated at gradient gemcitabine-equivalent concentrations was incubated in direct contact with triplicate monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for a period of either 96-hours or 182-hours. Anti-neoplastic cytotoxicity was measured using a MTT cell vitality assay relative to matched negative reference controls.
Mentions: Gemcitabine chemotherapeutic produced higher levels of anti-neoplastic cytotoxicity against chemotherapeutic resistant mammary adenocarcinoma during direct contact incubation periods of 182-hours compared to 96-hours especially at the gemcitabine-equivalent concentration of 10−6 M (Figure 4). Similarly, gemcitabine-(C4-amide)-[anti-EGFR] produced measurably higher levels of canti-neoplastic cytotoxicity when incubated with chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) for direct contact periods of 182-hours compared to 96-hours (Figure 5 and Figure 6).

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