tp-3654 and Colorectal-Neoplasms

Early and reliable diagnosis of colorectal cancer continues to be demanding and challenging. Colorectal cancer cells express Vasoactive Intestinal Peptide (VIP) receptors in high density. We have prepared a VIP analog (TP3654), labeled it with (99m)Tc, and evaluated it in experimental animals as an agent for imaging colorectal cancer. The tissue distribution of (99m)Tc-TP3654 has been compared with that of (111)In-DTPA-Octreotide and (99m)Tc-anti-CEA scan in nude mice bearing human colorectal cancer LS174T. Finally, pharmacokinetic and tissue distribution studies of (99m)Tc-TP3654 have been performed in four normal human volunteers. Data suggest that (99m)Tc-TP3654 can be prepared efficiently without loss of its receptor specificity and biological activity. Although the 24 hr tumor uptake of (99m)Tc-TP3654 in the animal model used was modest (0.21 +/- 0.07% I.D./g), the tissue distribution profile was more favorable than that of (111)In-DTPA-Octreotide or (99m)Tc-anti-CEA scan. Human studies indicated that (99m)Tc-TP3654 had no adverse effect in any subject. Within 24 hours, approximately 70% of the injected dose cleared through the kidneys, and approximately 20% through the hepatobiliary system. In these non-fasting volunteers hepatobiliary clearance was slow and in cancer patients tumor uptake was rapid. Data suggest that (99m)Tc-TP3654 is a promising agent for imaging colorectal cancer.

Topics: Colorectal Neoplasms; Humans; Indium Radioisotopes; Kidney; Octreotide; Oligopeptides; Quality Control; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Vasoactive Intestinal Peptide; Technetium; Tissue Distribution; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a naturally occurring 28-amino acid peptide with a wide range of biological activities. Recent reports suggest that VIP receptors are expressed on a variety of malignant tumor cells and that the receptor density is higher than for somatostatin. Our aims were to label VIP with 99mTc--a generator-produced, inexpensive radionuclide that possesses ideal characteristics for scintigraphic imaging--and to evaluate 99mTc-VIP for bioactivity and its ability to detect experimental tumors.. VIP28 was modified at the carboxy terminus by the addition of four amino acids that provided an N4 configuration for a strong chelation of 99mTc. To eliminate steric hindrance, 4-aminobutyric acid (Aba) was used as a spacer. VIP28 was labeled with 1251, which served as a control. Biological activity of the modified VIP28 agonist (TP3654) was examined in vitro using a cell-binding assay and an opossum internal anal sphincter (IAS) smooth muscle relaxivity assay. Tissue distribution studies were performed at 4 and 24 h after injection, and receptor-blocking assays were also performed in nude mice bearing human colorectal cancer LS174T. Blood clearance was examined in normal Sprague-Dawley rats.. The yield of 99mTc-TP3654 was quantitative, and the yields of 125I-VIP and 1251-TP3654 were >90%. All in vitro data strongly suggested that the biological activity of 99mTc-TP3654 agonist was equivalent to that of VIP28. As the time after injection increased, radioactivity in all tissues decreased, except in the receptor-enriched tumor (P = 0.84) and in the lungs (P = 0.78). The tumor uptake (0.23 percentage injected dose per gram of tissue [%ID/g]) was several-fold higher than 125I-VIP (0.06 %ID/g) at 24 h after injection in the similar system. In mice treated with unlabeled VIP or TP3654, the uptake of 99mTc-TP3654 decreased in all VIP receptor-rich tissues except the kidneys. The blood clearance was biphasic; the alpha half-time was 5 min and the beta half-time was approximately 120 min.. VIP28 was modified and successfully labeled with 99mTc. The results of all in vitro examinations indicated that the biological activity of TP3654 was equivalent to that of native VIP28 and tumor binding was receptor specific.

Topics: Animals; Binding, Competitive; Colorectal Neoplasms; Humans; In Vitro Techniques; Iodine Radioisotopes; Mice; Mice, Nude; Muscle Contraction; Muscle, Smooth; Neoplasm Transplantation; Oligopeptides; Opossums; Radionuclide Imaging; Rats; Rats, Sprague-Dawley; Receptors, Vasoactive Intestinal Peptide; Technetium; Transplantation, Heterologous; Tumor Cells, Cultured; Vasoactive Intestinal Peptide