Abstract:Salivary gland cancers (SGCs) frequently metastasize to cervical lymph nodes and distant organs. Currently, the mechanisms responsible for the metastatic behavior of SGC cells are not fully understood. We previously demonstrated that the stromal cell-derived factor-1 (SDF-1; also known as CXCL12)/CXCR4 system is involved in the establishment of metastasis in oral squamous cell carcinoma. In the present study, we investigated the role of CXCR4 in the metastatic behavior of SGCs. We examined the expression of CX… Show more
“…Pretreatment with 30 mg/kg Plerixafor® significantly reduced the tracer uptake in the tumor (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). Figure 1 shows that pretreatment with the CXCR4 antagonist also reduces tracer uptake in the salivary glands, which can be explained by the relatively high expression levels of the CXCR4 receptors in these glands [17]. Fig.…”
PurposeChemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[11C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[11C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer.ProcedureA subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[11C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V
T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BPND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated.ResultsThe tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[11C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V
T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V
T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BPND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED50 of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results.ConclusionN-[11C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V
T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.
“…Pretreatment with 30 mg/kg Plerixafor® significantly reduced the tracer uptake in the tumor (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). Figure 1 shows that pretreatment with the CXCR4 antagonist also reduces tracer uptake in the salivary glands, which can be explained by the relatively high expression levels of the CXCR4 receptors in these glands [17]. Fig.…”
PurposeChemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[11C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[11C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer.ProcedureA subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[11C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V
T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BPND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5–60 mg/kg) was investigated.ResultsThe tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[11C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V
T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V
T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BPND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED50 of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results.ConclusionN-[11C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V
T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.
“…In the common organs affected by metastatic pancreatic cancer, such as the liver and lungs, increased expression of CXCL12 has been demonstrated, suggesting that the CXCL12/CXCR4 axis serves a role in the organ-specific metastasis of cancer cells (28). The results of a previous study demonstrated that cancer cells metastasize along the concentration gradient of CXCL12 in salivary gland carcinoma (29). CXCR4 is essential in this process, and the application of CXCR4 antagonist ADM3100 could interrupt the metastasis of cancer cells.…”
Section: Discussionmentioning
confidence: 96%
“…CXCR4 is essential in this process, and the application of CXCR4 antagonist ADM3100 could interrupt the metastasis of cancer cells. CXCL12/CXCR4 has been revealed to serve an essential role in tumor cell chemotaxis, proliferation, invasion, angiogenesis, and in particular, organ-specific tumor metastasis (29). The overexpression of CXCR4 in tumor cells and the increased expression of CXCL12 in the cells of target organs facilitate tumor metastasis through the CXCL12/CXCR4 axis (30,31).…”
“…In our broader examination of the transcriptome of
angiogenic and nonangiogenic cell types, additional differences in gene expression
were observed. Many of the most highly upregulated genes in revertant clones have
been previously implicated in tumor progression and/or metastasis (35–43)
This might suggest that upregulation of these genes in revertant clones is a
secondary effect of the overall decrease in angiogenesis induced by these cells and
that the primary determinants of the reduced angiogenic stimulus remain to be
determined. Pathway and gene ontological analysis of differentially expressed genes
in angiogenic and revertant clones highlighted a number of possible mechanisms for
the differential ability of these cells to stimulate tumor growth beyond a
particular size.…”
The angiogenic switch, a rate-limiting step in tumor progression, has
already occurred by the time most human tumors are detectable. However, despite
significant study of the mechanisms controlling this switch, the kinetics and
reversibility of the process have not been explored. The stability of the
angiogenic phenotype was examined using an established human liposarcoma
xenograft model. Non-angiogenic cells inoculated into immunocompromised mice
formed microscopic tumors that remained dormant for ~125 days (vs. <40 days
for angiogenic cells) whereupon the vast majority (>95%) initiated
angiogenic growth with second-order kinetics. These original, clonally-derived
angiogenic tumor cells were passaged through four in vivo
cycles. At each cycle, a new set of single-cell clones was established from the
most angiogenic clone and characterized for in vivo for
tumorigenic activity. A total of 132 single-cell clones were tested in the 2nd,
3rd and 4th in vivo passage. Strikingly, at each passage, a
portion of the single-cell clones formed microscopic, dormant tumors. Following
dormancy, like the original cell line, these revertant tumors spontaneously
switched to the angiogenic phenotype. Finally, revertant clones were
transcriptionally profiles and their angiogenic output determined. Collectively,
these data demonstrate that the angiogenic phenotype in tumors is malleable and
can spontaneously revert to the non-angiogenic phenotype in a population of
human tumor cells.
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