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(Arg15, Arg21) VIP: evaluation of biological activity and localization to breast cancer tumors
T W Moody1, J Leyton, E Unsworth
1Cell & Cancer Biology Dept., Medicine Branch, National Cancer Institute, Rockville, MD 20850, USA. moodyt@bprb.nci.nih.gov
Abstract:
VIP analogs, which contain a single lysine amino acid, were synthesized and evaluated using breast cancer cells. (Arg15, Arg20) VIP, (Argl5, Arg21) VIP, and (Arg20, Arg21) VIP inhibited 125I-VIP binding to T47D cells with high affinity (IC50 values of 1.2, 1.0, and 0.8 nM, respectively). The VIP analogs elevated cAMP in T47D cells with ED50 values ranging from 0.1-1 nM. Because (Arg15, Arg21) VIP was the most potent at elevating cAMP, it was characterized further. (Arg15, Arg21) VIP transiently increased c-fos gene expression in breast cancer cells. N-Succinimidyl-4-18F (fluoromethly) benzoate was prepared in one chemical step from N-succinimidyl-4-(4-nitrobenzenesulfonyl)oxomethyl)benzoate by adding 18F in acetone at room temperature. This prosthetic group was then reacted with (Arg15, Arg21) VIP ((RR) VIP). (18F-RR) VIP bound with high affinity to T47D cells and was rapidly internalized. (18F-RR) VIP was injected intravenously into nude mice bearing breast cancer xenografts and after 4 h, the density of (18F-RR) VIP was elevated in the tumors relative to normal organs. These data suggest that VIP receptors may be used to localize breast cancer tumors.
Insights
Novel VIP analogs show promise for breast cancer detection. These analogs bind to VIP receptors, potentially enabling targeted imaging and localization of tumors.
Area of Science:
- Biochemistry
- Oncology
- Radiochemistry
Background:
- Vasoactive intestinal peptide (VIP) receptors are implicated in various cancers, including breast cancer.
- Targeting VIP receptors offers a potential strategy for breast cancer diagnosis and therapy.
Purpose of the Study:
- To synthesize and evaluate novel VIP analogs for their ability to bind VIP receptors and modulate cellular activity in breast cancer cells.
- To develop a radiolabeled VIP analog for potential use in breast cancer imaging.
Main Methods:
- Synthesis and characterization of VIP analogs with specific amino acid substitutions.
- Inhibition of radiolabeled VIP binding assays using T47D breast cancer cells.
- Measurement of cyclic AMP (cAMP) elevation in response to VIP analogs.
- Preparation of an 18F-labeled VIP analog using a novel prosthetic group.
- In vivo imaging studies in nude mice bearing breast cancer xenografts.
Main Results:
- Several VIP analogs demonstrated high-affinity binding to VIP receptors on T47D cells and effectively elevated cAMP levels.
- (Arg15, Arg21) VIP was identified as the most potent analog for cAMP elevation and c-fos gene expression.
- The 18F-labeled VIP analog, (18F-RR) VIP, exhibited high affinity binding, rapid internalization into T47D cells, and preferential accumulation in breast cancer xenografts in vivo.
- Tumor uptake of (18F-RR) VIP was significantly higher compared to normal organs in mice models.
Conclusions:
- VIP analogs can effectively target VIP receptors in breast cancer cells.
- The developed 18F-labeled VIP analog shows potential as a radiotracer for non-invasive imaging and localization of breast cancer.
- VIP receptors represent a promising target for the development of diagnostic tools for breast cancer.