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In vitro studies on interaction of 4-hydroperoxyifosfamide and 2-mercaptoethanesulphonate in malignant gliomas
A H Jäger1, U Bogdahn, R Apfel
1Department of Neurology, Julius-Maximilians-University, Würzburg, Germany.
Abstract:
Drug interference of ifosfamide and sodium 2-mercaptoethanesulphonate (MESNA) was studied in three malignant glioma cell cultures (HTZ-17, HTZ-209B, and HTZ-243) by a recently developed in vitro method for evaluation of multimodal treatment interactions. Glioma cell cultures were treated in monolayer 96-well tissue-culture plates for 2 h each, with 4-hydroperoxyifosfamide and MESNA combined in both sequences, or alone. Concentrations ranged from 0.01 microM to 50 microM in single-modality exposures, and from 0.01 microM to 10 microM in combination exposures. After five population doubling times, DNA synthesis was determined by a standard [3H]Tdr-incorporation liquid-scintillation-counting protocol. Data points were evaluated for mono- and combined treatment dose effects (adapted with a probit function), and a model-free three-dimensional response surface was created that was compared to the theoretical additive, anticipated response surface. Local additivity was analysed for any ratio of combined treatment. No tumour effects were seen with MESNA in single-drug exposure, whereas ifosfamide resulted in more than 90% inhibition of tumour DNA synthesis. In combination experiments, MESNA could be confirmed to be inert: the anticipated theoretical combination response surfaces formed a three-dimensional extension of the single-drug ifosfamide dose/response curves--the experimental combination response surfaces displayed an identical appearance (P < or = 0.05). In conclusion, these results indicate no drug interference of MESNA and ifosfamide in malignant glioma cells.
Insights
Sodium 2-mercaptoethanesulphonate (MESNA) does not interfere with ifosfamide treatment in malignant glioma cells. MESNA was found to be inert, showing no impact on ifosfamide
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Malignant gliomas are aggressive brain tumors.
- Ifosfamide is a chemotherapy agent used in cancer treatment.
- Sodium 2-mercaptoethanesulphonate (MESNA) is often co-administered with ifosfamide to mitigate toxicity.
Purpose of the Study:
- To evaluate potential drug interference between ifosfamide and MESNA in malignant glioma cells.
- To assess the in vitro interaction of 4-hydroperoxyifosfamide and MESNA on glioma cell DNA synthesis.
Main Methods:
- Utilized a novel in vitro method to study drug interactions in three malignant glioma cell lines (HTZ-17, HTZ-209B, HTZ-243).
- Cells were exposed to varying concentrations of 4-hydroperoxyifosfamide and MESNA, alone and in combination.
- DNA synthesis was quantified via [3H]Tdr incorporation after five population doublings.
Main Results:
- MESNA alone showed no significant effect on tumor cell DNA synthesis.
- Ifosfamide alone inhibited tumor DNA synthesis by over 90%.
- In combination, MESNA did not alter the dose-response of ifosfamide, confirming its inertness and lack of interference (P < 0.05).
Conclusions:
- MESNA does not interfere with the anti-tumor activity of ifosfamide in malignant glioma cells.
- The combination of ifosfamide and MESNA demonstrates an additive effect, consistent with ifosfamide's single-agent activity.
- This study supports the continued use of MESNA with ifosfamide in glioma treatment without compromising efficacy.