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An adsorptive transfer technique coupled with brdicka reaction to reveal the importance of metallothionein in chemotherapy with platinum based cytostatics.

Krizkova S, Fabrik I, Huska D, Adam V, Babula P, Hrabeta J, Eckschlager T, Pochop P, Darsova D, Kukacka J, Prusa R, Trnkova L, Kizek R - Int J Mol Sci (2010)

Bottom Line: The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents.This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo.The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.

ABSTRACT
The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents. Thanks to many clinical studies it is known that resistance of tumor cells to drugs is a frequent cause of chemotherapy failure. With regard to platinum based drugs, multidrug resistance can also be connected with increased expression of low-molecular weight protein metallothionein (MT). This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo. The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT. Further, we analyzed extracts of neuroblastoma cell lines treated with cisplatin or carboplatin. It is clear that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of the platinum-based cytostatics cisplatin and carboplatin. Finally, we determined the level of MT in samples from rabbits treated with carboplatin and patients with retinoblastoma treated with the same drug.

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Neuroblastoma cell culture. Dependence of MT level in cell lines on the length of the cultivation. Prior to use in this experiment, all cell lines were cultivated for five sub-cultivations without cytostatics addition. Then, neuroblastoma cell cultures were exposed to cisplatin (left) or carboplatin (right).
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f5-ijms-11-04826: Neuroblastoma cell culture. Dependence of MT level in cell lines on the length of the cultivation. Prior to use in this experiment, all cell lines were cultivated for five sub-cultivations without cytostatics addition. Then, neuroblastoma cell cultures were exposed to cisplatin (left) or carboplatin (right).

Mentions: Sensitive cell lines demonstrated a significant growth depression in the presence of cytostatic agents. MT level was significantly increased in all sensitive tumor cell lines by about 50–90% in comparison with the control cell line. As it is well evident from Figure 5, the MT level increased in resistant tumor cell lines compared to sensitive cells. In the resistant tumor cell lines, the increase of MT level was dependent on the cytostatic agent used and its concentration. With carboplatin, changes in MT level were observable from the beginning of the experiment, whereas under the two highest carboplatin concentrations the MT level was significantly increased in resistant tumor cells compared to sensitive ones. In the case of the cisplatin-resistant tumor cell line, the MT level increase was firstly observable after six hours of treatment. This increase was consequently followed by a moderate decrease in comparison with the resistant tumor cell line, whose maximum MT level was well evident already in the first hours of the experiment. Then, MT level relatively rapidly decreased to that of the values of sensitive tumor cell lines. Fluctuation in MT after cisplatin as well as carboplatin exposition with a similar development in the presence of all applied concentrations can be interpreted by initiatory free MT saturation by cytostatic agent and its resulting elimination from cells, which results in a decrease of MT level in cells. Resistant tumor cell lines, in contrast to the sensitive ones, responded to the cytostatic agent presence by significantly enhancing MT expression, which was well evident as a rapid increase of the MT level. Determined differences in MT levels during platinum-based cytostatics treatment are in good agreement with our knowledge about cytostatics detoxification via thiol compounds that increase the ability of these tumor cell lines to survive in the presence of platinum-based therapeutics. From the obtained results, it clearly follows that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of platinum-based cytostatics cisplatin and carboplatin.


An adsorptive transfer technique coupled with brdicka reaction to reveal the importance of metallothionein in chemotherapy with platinum based cytostatics.

Krizkova S, Fabrik I, Huska D, Adam V, Babula P, Hrabeta J, Eckschlager T, Pochop P, Darsova D, Kukacka J, Prusa R, Trnkova L, Kizek R - Int J Mol Sci (2010)

Neuroblastoma cell culture. Dependence of MT level in cell lines on the length of the cultivation. Prior to use in this experiment, all cell lines were cultivated for five sub-cultivations without cytostatics addition. Then, neuroblastoma cell cultures were exposed to cisplatin (left) or carboplatin (right).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3100849&req=5

f5-ijms-11-04826: Neuroblastoma cell culture. Dependence of MT level in cell lines on the length of the cultivation. Prior to use in this experiment, all cell lines were cultivated for five sub-cultivations without cytostatics addition. Then, neuroblastoma cell cultures were exposed to cisplatin (left) or carboplatin (right).
Mentions: Sensitive cell lines demonstrated a significant growth depression in the presence of cytostatic agents. MT level was significantly increased in all sensitive tumor cell lines by about 50–90% in comparison with the control cell line. As it is well evident from Figure 5, the MT level increased in resistant tumor cell lines compared to sensitive cells. In the resistant tumor cell lines, the increase of MT level was dependent on the cytostatic agent used and its concentration. With carboplatin, changes in MT level were observable from the beginning of the experiment, whereas under the two highest carboplatin concentrations the MT level was significantly increased in resistant tumor cells compared to sensitive ones. In the case of the cisplatin-resistant tumor cell line, the MT level increase was firstly observable after six hours of treatment. This increase was consequently followed by a moderate decrease in comparison with the resistant tumor cell line, whose maximum MT level was well evident already in the first hours of the experiment. Then, MT level relatively rapidly decreased to that of the values of sensitive tumor cell lines. Fluctuation in MT after cisplatin as well as carboplatin exposition with a similar development in the presence of all applied concentrations can be interpreted by initiatory free MT saturation by cytostatic agent and its resulting elimination from cells, which results in a decrease of MT level in cells. Resistant tumor cell lines, in contrast to the sensitive ones, responded to the cytostatic agent presence by significantly enhancing MT expression, which was well evident as a rapid increase of the MT level. Determined differences in MT levels during platinum-based cytostatics treatment are in good agreement with our knowledge about cytostatics detoxification via thiol compounds that increase the ability of these tumor cell lines to survive in the presence of platinum-based therapeutics. From the obtained results, it clearly follows that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of platinum-based cytostatics cisplatin and carboplatin.

Bottom Line: The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents.This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo.The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.

ABSTRACT
The drugs based on platinum metals represent one of the oldest, but also one of the most effective groups of chemotherapeutic agents. Thanks to many clinical studies it is known that resistance of tumor cells to drugs is a frequent cause of chemotherapy failure. With regard to platinum based drugs, multidrug resistance can also be connected with increased expression of low-molecular weight protein metallothionein (MT). This study aimed at investigating the interactions of MT with cisplatin or carboplatin, using the adsorptive transfer technique coupled with differential pulse voltammetry Brdicka reaction (AdTS DPV Brdicka reaction), and a comparison of in vitro results with results obtained in vivo. The results obtained from the in vitro study show a strong affinity between platinum based drugs and MT. Further, we analyzed extracts of neuroblastoma cell lines treated with cisplatin or carboplatin. It is clear that neuroblastoma UKF-NB-4 cisplatin-resistant and cisplatin-sensitive cell lines unlikely respond to the presence of the platinum-based cytostatics cisplatin and carboplatin. Finally, we determined the level of MT in samples from rabbits treated with carboplatin and patients with retinoblastoma treated with the same drug.

Show MeSH
Related in: MedlinePlus