Imatinib pharmacokinetics and creatine kinase levels in chronic myeloid leukemia patients: implications for therapeutic response and monitoring.

BACKGROUND: Imatinib treatment for certain cancers can lead to elevated creatine kinase (CK) levels, potentially indicating muscle injury, and ongoing research aims to understand the correlation between imatinib levels and creatine kinase to assess its impact on treatment response. METHODS: This single-center observational study involved 76 chronic myeloid leukemia (CML) patients receiving imatinib treatment, focusing on evaluating drug and metabolite levels using liquid chromatography-mass spectrometry (LC-MS-MS) instrumentation. Serum CK and creatine kinase-MB (CK-MB) levels were assessed using Colorimetric kits. RESULTS: CK and CK-MB levels were measured, CK showed a median value of 211.5 IU/l and CK-MB showed a median value of 4.4 IU/l. Comparing low and high CK groups, significant differences were found in peak and trough plasma concentrations of imatinib and its metabolites. Correlations between CK levels and pharmacokinetic parameters were explored, with notable associations identified. Binary logistic regression revealed predictors influencing the therapeutic response to imatinib and categorized expected CK levels into high or low, with peak levels of imatinib emerging as a significant predictor for CK level categorization. CONCLUSION: The study highlights the link between imatinib's pharmacokinetics and elevated CK levels, indicating a possible correlation between specific metabolites and improved treatment response. Individualized monitoring of CK levels and imatinib pharmacokinetics could enhance care for CML patients.

Effect of l-carnitine on cardiotoxicity and apoptosis induced by imatinib through PDGF/ PPARγ /MAPK pathways.

A tyrosine kinase inhibitor Imatinib (IM) is used in the treatment of different varieties of cancers. The current study was designed to explore the beneficial role of l-carnitine against IM-induced cardiotoxicity in rats. Male albino rats received IM (40 mg/kg, i.p.) either alone or/in combination with l-carnitine (100 mg/kg, i.p.) for 7 days. IM increased serum inflammatory cytokines, concomitant with activation of cardiac MAPK, α-SMA, malondialdehyde (MDA) and nitric oxide(NO), decreased cardiac peroxisome proliferator-activated receptor-γ (PPAR-γ) level, superoxide dismutase (SOD) activity, and glutathione (GSH) content. The expression levels of Bcl-2 and PDGF were significantly decreased, while the expression levels of CTGF and BAX were significantly increased in the IM group. The l-carnitine treatment successfully protected the heart as indicated by the improvement of the biochemical and histopathological parameters. l-carnitine didn't affect the serum concentration of IM and increased intracellular concentration in the combination-treated group as measured by the mass spectrometer. Conclusion: l-carnitine abrogated IM-induced cardiac damage and apoptosis via PDGF/PPARγ/MAPK pathways.

Evaluation of tamoxifen and simvastatin as the combination therapy for the treatment of hormonal dependent breast cancer cells.

Tamoxifen (TAM) is a nonsteroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM), a lipid-lowering agent, has been shown to inhibit cancer cell growth. The study aimed at investigating the impact of using SIM with TAM in estrogen receptor-positive (ER+) breast cancer cell line, T47D, as well as in mice-bearing Ehrlich solid tumor. The cell line was treated with different concentrations of TAM or/and SIM for 72 h. The effects of treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated. Our results showed that the combination treatment decreased the oxidative stress markers, glucose uptake, VEGF, and MMP 2 &9 in the cell line compared to TAM- treated cells. Drug interaction of TAM and SIM was synergistic in T47D by increasing the apoptotic makers Bax/BCL-2 ratio and caspase 3 activity. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume compared to TAM treated group. Moreover, the combined treatment decreased the protein expression of TNF-α, NF-kB compared to control. In conclusion, our results suggest that SIM may serve as a promising treatment with TAM for improving the efficacy against estrogen receptor-positive (ER+) breast cancer.

Simvastatin Evokes An Unpredicted Antagonism For Tamoxifen In MCF-7 Breast Cancer Cells.

PURPOSE: Tamoxifen (TAM) is a non-steroidal antiestrogen drug, used in the prevention and treatment of all stages of hormone-responsive breast cancer. Simvastatin (SIM) is a lipid-lowering agent and has been shown to inhibit cancer cell growth. The study aimed to investigate the effect of the combination of TAM and SIM in the treatment of estrogen receptor positive (ER+) breast cancer cell line, MCF-7, and in mice-bearing Ehrlich solid tumors. METHODS: MCF-7 cells were treated with different concentrations of TAM or/and SIM for 72 hours and the effects of the combination treatment on cytotoxicity, oxidative stress markers, apoptosis, angiogenesis, and metastasis were investigated using different techniques. In addition, tumor volume, oxidative markers, and inflammatory markers of the combined therapy were explored in mice bearing solid EAC tumors. RESULTS: The results showed that treatment of MCF-7 cells with the combination of 10 µM TAM, and 2 µM SIM significantly inhibited the increase in oxidative stress markers, LDH, and NF-kB induced by TAM. In addition, there was a significant decrease in the total apoptotic ratio, caspase-3 activity, and glucose uptake, while there was a non-significant change in Bax/bcl-2 ratio compared to the TAM-treated group. Using the isobologram equation, the drug interaction was antagonistic with combination index, CI=1.18. On the other hand, the combination regimen decreased VEGF, and matrix metalloproteinases, MMP 2&9 compared to TAM-treated cells. Additionally, in vivo, the combination regimen resulted in a non-significant decrease in the tumor volume, decreased oxidative markers, and the protein expression of TNF-α, and NF-κB compared to the TAM treated group. CONCLUSION: Although the combination regimen of TAM and SIM showed an antagonistic drug interaction in MCF-7 breast cancer, it displayed favorable antiangiogenic, anti-metastatic, and anti-inflammatory effects.