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Use of Radiolabeled Bombesin in Humans

Department of Scienze Radiologiche, Università "La Sapienza" Rome, Italy

Alexandra D. Varvarigou

National Center for Scientific Research "Demokritos," Athens, Greece

To the Editor:

The Journal of Clinical Oncology has recently published an interesting and rather complete review by Van Den Booshe and Van de Wiele¹ on the current status of receptor imaging in oncology. In the section on bombesin, gastric releasing peptide receptors, the authors write that several radiolabeled bombesin analogs have been developed for in vivo imaging, but only RP 527 has been studied on metastatic breast and prostate cancer, with limited diagnostic results: uptake occurred in four of six patients with breast cancer and in one of four patients with prostate cancer metastases. This statement does not allow readers to understand the successful work carried out by different basic and clinical research centers, which studied cancer overexpression of bombesin receptors in humans for diagnostic purposes. These studies have shown that labeled bombesin helps early diagnosis, as well as staging of several cancers with a simple, noninvasive scintigraphic examination.

Since 2002, Scopinaro et al^2,3 and De Vincentis et al⁴ have shown the usefulness of 99m-technetium (^99mTc)-[13leu]bombesin in several cancer patients. Scopinaro et al studied 15 patients with mammographic lesions who underwent biopsy and/or operation. ^99mTc bombesin (^99mTc-BN) correctly diagnosed 12 of 15 breast cancers, while scintigraphy was negative in three of three benign lesions.⁵ Soluri et al guided a mammotome biopsy with ^99mTc-BN, with five of five yielding successful results.⁶ Using ^99mTc-BN, Scopinaro et al diagnosed eight of eight primary prostate cancers and correctly detected node invasion in three patients, in whom computed tomography and magnetic resonance imaging were negative or inconclusive. Moreover, they obtained two of two true-negative scans in benign prostate lesions, while Hoffman et al used positron emission tomography with 68-gallium (⁶⁸Ga) -BN to diagnose 13 prostate cancers. De Vincentis et al,^9,10 in a population of 14 subjects, obtained 12 true-positive prostate cancers, four of which were correctly diagnosed as metastatic. Five of 14 of those patients were also imaged with 111-indium (¹¹¹In) octreotide (¹¹¹In OC) and ^99mTc BN, showing how only some metastases in the same subject are able to take up these radiopeptides. This method will probably be able to differentiate metastases with glandular cancer from metastases with neuroendocrine shift; the study of De Vincentis suggests a role of ^99mTc BN/¹¹¹In OC in characterizing prostate metastases and also in studying the process of neuroendocrine shift.

Scopinaro et al^11,12 showed that fast uptake of ^99mTc-BN makes possible the study of colorectal cancer within 50 minutes postinjection, before the arrival of labeled peptide from liver into intestine, with 94.1% sensitivity and 67% specificity on 13 patients. ^99mTc BN scan led to change of medical decision about surgical or radiation therapy in five of seven patients with rectal cancer. The ability of ^99mTc BN to drive surgery has finally been tested by De Vincentis on miscellaneous cancers. Of course we are reporting published results: other cancers, such as small-cell lung and pancreas cancers are being studied by us and probably by the other researchers who got useful results.

At doses lower than 70 µg of intravenously injected peptide, the only observed side effect was transitory increase of blood pressure of 10 to 20 mmHg in a few patients. Published full articles or abstracts of international congresses report more than 50 patients studied with labeled BN; this is more than a phase I or a feasibility study.

Since the binding site of BN to its receptors is the peptide C terminus, two main ways have been used by radiopharmacists in order to link radioactive metals to BN without changing its properties: the first is the most common method of linking a bifunctional chelating agent to the N-terminus of the peptide; the second method is to synthesize a peptide modified in the N- terminus so that the N-terminus is by itself able to link the radioactive metals. Van de Wiele et al¹³ and Hoffman et al⁸ used peptides labeled with the first method, Scopinaro et al,^{2,3,5,7,11,12} Soluri et al,⁶ and De Vincentis et al^4,9,10 used the bombesin-like peptide synthesized by Varvarigou et al^14,15 with the second method. It is not at the moment possible to assess that one method is superior or more promising than others. It is on the contrary very probable that both methods can open a new horizon for cancer therapy, allowing bombesin/gastrin-releasing peptide to be labeled with beta-emitting isotopes, which are able to deliver therapeutic radiation doses inside several tumors.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest

REFERENCES

1. Van Den Bossche B, Van de Wiele C: Receptor imaging in oncology by means of nuclear medicine: Current status. J Clin Oncol 22:3593-3607, 2004[Abstract/Free Full Text]

2. Scopinaro F, Varvarigou AD, Ussof W, et al: Technetium labeled bombesin-like peptide: Preliminary report on breast cancer uptake in patients. Cancer Biother Radiopharm. 17:327-335, 2002[CrossRef][Medline]

3. Scopinaro F, Varvarigou A, Ussof W, et al: Breast cancer takes up 99mTc bombesin: A preliminary report. Tumori 88:S25-S28, 2002[Medline]

4. De Vincentis G, Scopinaro F, Varvarigou A, et al.: Phase I trial of technetium [Leu13] bombesin as cancer seeking agent: Possible scintigraphic guide for surgery? Tumori 88:S28-S30, 2002[Medline]

5. Scopinaro F, De Vincentis G, Ussof W, et al.: Prone scintimammography with 13Leu Bombesin Tc-99m: Comparison with sestamibi scintimammography. Eur J Nucl Med 29:S68, 2002 (abstr 80; suppl 1)

6. Soluri A, Scopinaro F, De Vincentis G, et al.: 99MTc [13LEU] bombesin and a new gamma camera, the imaging probe, are able to guide mammotome breast biopsy. Anticancer Res 23:2139-2142, 2003[Medline]

7. Scopinaro F, De Vincentis G, Varvarigou AD, et al: 99mTc-bombesin detects prostate cancer and invasion of pelvic lymph nodes. Eur J Nucl Med Mol Imaging 30:1378-1382, 2003[CrossRef][Medline]

8. Hofmann M, Machtens S, Stief C, et al: Feasibility of Ga-68-DOTABOM PET in prostate carcinoma patients. Eur J Nucl Med Mol Imaging 31:S253, 2004 (abstr 207; suppl 2)

9. De Vincentis G, Remediani S, Varvarigou AD, et al: Role of 99mTc-Bombesin scan in diagnosis and staging of prostate cancer. Cancer Biother Radiopharm 18:285, 2003 (abstr)

10. De Vincentis G, Remediani S, Varvarigou AD, et al: Role of 99mTc-Bombesin scan in diagnosis and staging of prostate cancer. Cancer Biother Radiopharm 19:81-84, 2004[Medline]

11. Scopinaro F, De Vincentis G, Corazziari E et al.: Detection of colon cancer with 99mTc- bombesin (99mTc-BN). Cancer Biother Radiopharm 18:293. 2003 (abstr)

12. Scopinaro F, De Vincentis G, Corazziari E, et al: Detection of colon cancer with 99mTc-labeled bombesin derivative (99mTc-leu13-BN1). Cancer Biother Radiopharm. 19:245-252, 2004[Medline]

13. Van de Wiele C, Dumont F, Vanden Broecke R, et al: Technetium-99m RP527, a GRP analogue for visualisation of GRP receptor-expressing malignancies: A feasibility study. Eur J Nucl Med 27:1694-1699, 2000[CrossRef][Medline]

14. Varvarigou AD, Scopinaro F, Leondiadis L, et al: Synthesis, chemical, radiochemical and radiobiological evaluation of a new 99mTc-labelled bombesin-like peptide. Cancer Biother Radiopharm 17:317-326, 2002[Medline]

15. Varvarigou A, Bouziotis P, Zikos C, et al: Gastrin-releasing peptide (GRP) analogues for cancer imaging. Cancer Biotherapy Radiopharm 19:219-229, 2004

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