Purpose: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents.
Experimental Design: Uptake of [(3)H]sorafenib or [(3)H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters.
Results: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 micromol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls.
Conclusions: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-0048 | DOI Listing |
Biofactors
December 2024
Department of Gynecology, Affiliated Hospital of Nantong University, Nantong, China.
Tumor angiogenesis and the presence of cancer stem cells (CSCs) are critical characteristics of tumors. Previous research has demonstrated that cancer stem cells promote tumor angiogenesis, while increased vascularity, in turn, fosters the growth of cancer stem cells. This creates a detrimental cycle that contributes to tumor progression.
View Article and Find Full Text PDFDiscov Oncol
December 2024
Department of Medical Oncology Laboratory, All India Institute of Medical Sciences, New Delhi, India.
Thyroid cancer (TC) being the common endocrine malignancy is glooming steadily due to its poor prognosis. The treatment strategies of surgery, radiotherapy, and conventional chemotherapy are providing unsatisfactory output. However, combination therapy can negotiate the worse prognosis to the better, where chemoradiotherapy, radiotherapy with surgery, or dual chemotherapeutic drugs are being glorified.
View Article and Find Full Text PDFFront Pharmacol
October 2024
Department of Pharmacy, Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
Objective: To optimize the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for cancer patients, we characterized and evaluated ONJ related to TKIs and ICIs by analyzing a public database and reviewing the relevant literature. TKIs and ICIs are limited to drugs that treat renal cancer recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Kidney Cancer.
Methods: We described a case series of patients experiencing ONJ while on TKIs or ICIs.
J Mol Recognit
January 2025
Department of Molecular Biology and Genetics, Istanbul AREL University, Istanbul, Turkey.
Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors.
View Article and Find Full Text PDFRSC Adv
September 2024
SVAK Life Sciences ALEAP Industrial Area, Pragathi Nagar Hyderabad - 500090 India
A novel series of 20 compounds containing 4-aminopyrazolo[3,4-]pyrimidine core were synthesized, characterized and their chemical structures confirmed using spectroscopic techniques such as H NMR, C NMR, IR, and HRMS. The compound's growth inhibitory activities were evaluated against 60 human tumor cell lines from nine panels: leukemia, non-small cell lung cancer (NSCLC), colon, central nervous system (CNS), melanoma, ovarian, renal, prostate, and breast cancer. Among all the compounds, 11, 12c, 12d, 12f, and 12j are active against different cancer cell lines.
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