99mTc labeled VIP analog: evaluation for imaging colorectal cancer

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Abstract

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 99mTc, and evaluated it in experimental animals as an agent for imaging colorectal cancer. The tissue distribution of 99mTc-TP3654 has been compared with that of 111In-DTPA-Octreotide and 99mTc-anti-CEA scan in nude mice bearing human colorectal cancer LS174T. Finally, pharmacokinetic and tissue distribution studies of 99mTc-TP3654 have been performed in four normal human volunteers. Data suggest that 99mTc-TP3654 can be prepared efficiently without loss of its receptor specificity and biological activity. Although the 24 hr tumor uptake of 99mTc-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 111In-DTPA-Octreotide or 99mTc-anti-CEA scan. Human studies indicated that 99mTc-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 99mTc-TP3654 is a promising agent for imaging colorectal cancer.

Introduction

Colorectal cancer is a major health care problem in the United States, with more than 165,000 new cases diagnosed each year [5], [9], [10], [14], [32]. It is a primary cause of 10% of all cancer-related deaths. The overall mortality rate of newly diagnosed large-bowel cancer approaches 50%. Approximately 30% of patients with colorectal cancer have unresectable disease at presentation, and 33% develop metastases during the course of their disease [2], [14], [24], [29], [30].

Recent advances in oncology have made early tumor diagnosis and staging essential in the management of patients with colorectal cancers. Medical literature abounds with evidence that early detection and aggressive treatment of these lesions can improve patient survival. The use of CT, MRI, and Ultrasound are an integral part of evaluation of these patients and can detect large, residual, and recurrent tumors. However, these techniques have limitations in the staging of disease, particularly with regard to recurrent or metastatic lesions [8], [28]. While initial evidence suggests that high signal intensity on T2-weighted MRI images would be specific for recurrent or metastatic lesions, more recent reports raise serious concerns about the ability of MRI to distinguish colorectal tumors from a benign mass of fibrotic or inflammatory tissue [8]. Pseudolesions produced false positive findings at CT colography [12]. Dual phase helical CT does not appear to improve detection of liver metastases secondary to colorectal cancer [7].

Positron Emission Tomography (PET) using 18F-fluorodeoxy glucose has a high sensitivity and specificity for detection of colorectal carcinomas and appears to be superior to CT [1], [11], [22]. However, this agent as yet has limited availability and requires specially designed scanning devices.

A large number of radiolabeled monoclonal antibodies have been evaluated to image colorectal cancer and one, 99mTc-F(ab′) of a anti-CEA antibody IMMU-4 (99mTc-Arcituromab), has become available commercially [13], [17], [35]. In many instances, promising results in detecting and staging recurrent tumors have been reported. However, metastases to lymph nodes and liver are not detectable with an acceptable degree of accuracy.

The long acting somatostatin analog 111In-DTPA-(D)-Phe1-Octreotide has been successfully used for imaging endocrine and other tumors [18], [19], [20], [21]. However, it has been [34] reported that Octreoscan was positive only in four out of seventeen colonic adenocarcinoma patients, all of whom were found to be correctly positive with I-123 labeled Vasoactive Intestinal Peptide (VIP) [34]. These results are consistent with the independent studies of Reubi [25], [26] who, using in vitro autoradiographic technique, reported that the VIP receptor density on human colonic tumors is approximately 2.5 times higher than the somatostatin receptor density. These complementary data from two independent studies strongly suggest that radiolabeled VIP could be a valuable agent for imaging VIP receptor rich adenocarcinomas of the colon and their metastatic lesions.

Considering the attractive physical characteristics (t12 = 6 hrs, γ-140 KeV, 90%) and its global availability from a generator system, we have used 99mTc to label VIP. The preparation yields of 99mTc-VIP (99mTc-TP3654) were greater than 95% and when analyzed using reverse phase HPLC the compound was eluted as a single peak [23]. In vitro results and evaluation in experimental animals showed that the biological activity and receptor specificity of 99mTc-TP3654 were not compromised and that the radioactivity uptake in experimental tumors was receptor specific [23].

The purpose of this study was to evaluate the use of 99mTc-TP3654 as an agent for imaging colorectal cancer in experimental animals and compare its efficacy with 111In-D-Phe′-Octreotide and 99mTc-anti-CEA scan.

Section snippets

VIP and synthesis of its analogs

VIP is a 28 amino acid peptide initially isolated from porcine intestine some 25 years ago [27]. VIP28, whose structure is common in humans, pigs, and rats, is a hydrophobic, basic peptide containing three lysine (no. 15, 20, and 21), two arginine (no. 12 and 14), and two tyrosine (no. 10 and 22) residues. In our early attempt to label VIP28 with 99mTc, we had adapted the conventional bifunctional chelating agent (BFCA) approach. In this approach we had synthesized two BFCAs, namely CPTA

Results

The labeling efficiency of 99mTc-CTPA-VIP ranged between 35–50% (N = 7) and that for 99mTc-MAG3-VIP between 50–70% (N = 4). The HPLC elution profile showed several peaks with 99mTc-CPTA-VIP and two prominent peaks with 99mTc-MAG3-VIP. These results indicated that preparations were radiochemically impure.

The yields of 99mTc-TP3654 were greater than 95% (N = 25). By HPLC, the 99mTc-TP3654 radioactivity was eluted as a single peak at Rt 11.8 min. Free 99mTc was less than 5% and colloid less than

Discussion

Imaging tumors with 99mTc labeled receptor specific biomolecules can be more specific than anatomic or metabolic imaging. Receptor specific imaging may lead investigators to monitor the effectiveness of surgical or therapeutic intervention and may even promise to detect pre-cancerous cells in vivo [31]. With a combination of suitable radionuclides, receptor specific biomolecules can not only be used for detecting tumors, but also for treating them therapeutically. Therefore, development of such

Conclusion

A 99mTc-labeled VIP analog, TP3654, appears to be a promising agent for imaging colorectal cancer, which expresses VIP receptors in high density. In experimental animals, the agent had higher tumor uptake (P = <0.05) than that of 111In-DTPA-Octreotide. Although this tumor uptake was lower than that of 99mTc-anti-CEA scan, the overall tissue distribution of 99mTc-TP3654 was more favorable because it had significantly lower uptake than 99mTc-anti-CEA scan in all normal organs, including

Acknowledgements

The work was supported in part by 1R41CA82043-01. We thank Ms. Katherine Musselman for preparation of the manuscript.

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