Abstract
An approach to image radiolabeled peptide localization at tumor sites by inducing tumor cells to synthesize membrane expressed human somatostatin receptor subtype 2 (hSSTr2) with a high affinity for radiolabeled somatostatin analogues is described. The use of gene transfer technology to induce expression of high affinity membrane hSSTr2 can enhance the specificity and degree of radiolabeled peptide localization in tumors. Employing this strategy, induction of high levels of hSSTr2 expression with selective tumor uptake of radiolabeled peptides was achieved in both subcutaneous non-small cell lung cancer and intraperitoneal ovarian cancer mouse human tumor xenograft models. The features of this genetic transduction imaging approach are: (1) constitutive expression of a tumor-associated receptor is not required; (2) tumor cells are altered to express a new target receptor or increased quantities of a constitutive receptor at levels which may significantly increase tumor targeting of radiolabeled peptides compared to uptake in normal tissues; (3) gene transfer can be accomplished by local or regional injection of adenoviral vectors; (4) it is feasible to target adenovirus vectors to tumor cells by modifying adenoviral tropism (binding) or by the use of tumor-specific promoters such that the hSSTr2 will be specifically expressed in the desired tumor; and (5) this technique can be used to image expression of a second therapeutic gene.
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Patel YC. Somatostatin and its receptor family.Front Neuroendocrinol 1999; 20: 157–198.
Reubi JC, Schaer JC, Waser B, Mengod G. Expression and localization of somatostatin receptor SSTR1, SSTR2, and SSTR3 messenger RNAs in primary human tumors usingin situ hybridization.Cancer Res 1994; 54: 3455–3459.
Woltering EA, O’Dorisio MS, O’Dorisio TM. The role of radiolabeled somatostatin analogs in the management of cancer patients. In:Principles and Practice of Oncology, PPO Updates, DeVita Jr VT, Hellman S, Rosenberg SA, eds., Vol. 9. Philadelphia; Lippincott-Raven, 1995: 1–16.
Reubi JC, Waser B, Schaer JC, Markwalder R. Somatostatin receptors in human prostate and prostate cancer.J Clin Endocrinol Metab 1995; 80: 2806–2814.
Nilsson S, Reubi JC, Kalkner KM, Laissue JA, Horisberger U, Olerud C, et al. Metastatic hormone-refractory prostatic adenocarcinoma expresses somatostatin receptors and is visualizedin vivo by [111In]-labeled DTPA-D-[Phe1]-octreotide scintigraphy.Cancer Res 1995; 55 (Suppl): 5805s-5810s.
Halmos G, Schally AV, Sun B, Davis R, Bostwick DG, Plonowski A. High expression of somatostatin receptors and messenger ribonucleic acid for its receptor subtypes in organ-confined and locally advanced human prostate cancers.J Clin Endocrinol Metab 2000; 85: 2564–2571.
Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney.Proc Natl Acad Sci USA 1992; 89: 251–255.
Hoyer D, Bell GI, Berelowitz M, Epelbaum J, Feniuk W, Humphrey PP, et al. Classification and nomenclature of somatostatin receptors.Trends Pharmacol Sci 1995; 16:: 86–88.
Feuerbach D, Fehlmann D, Nunn C, Siehler S, Langenegger D, Bouhelal R, et al. Cloning, expression and pharmacological characterisation of the mouse somatostatin sst(5) receptor.Neuropharmacology 2000; 39: 1451–1462.
Virgolini I, Leimer M, Handmaker H, Lastoria S, Bischof C, Muto P, et al. Somatostatin receptor subtype specificity andin vivo binding of a novel tumor tracer,99mTc-P829.Cancer Res 1998; 58: 1850–1859.
Manchanda R, Azure M, Lister-James J, Bush L, Zinn K, Baggs R, et al. Tumor Regression in rat pancreatic (AR42J) tumor-bearing mice with Re-188 P2045-A somatostatin analog.Clin Cancer Res 1999; 5: 3769s.
Reubi JC, Schär JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use.Eur J Nucl Med 2000; 27: 273–282.
Virgolini I, Kurtaran A, Raderer M, Leimer M, Angelberger P, Havlik E, et al. Vasoactive intestinal peptide receptor scintigraphy.J Nucl Med 1995; 36: 1732–1739.
Lamberts SWJ, van der Lely A-J, de Herder WW, Hofland LJ. Octreotide.N Engl J Med 1996; 334: 246–254.
Blum JE, Handmaker H, Rinne NA. The utility of a soma-tostatin-type receptor binding peptide radiopharmaceutical (P829) in the evaluation of solitary pulmonary nodules.Chest 1999; 115: 224–232.
Traub T, Petkov V, Ofluoglu S, Pangerl T, Raderer M, Fueger BJ, et al.111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung.J Nucl Med 2001; 42:: 1309–1315.
Rogers BE, Garver RI Jr, Grizzle WE, Buchsbaum DJ. Genetic induction of antigens and receptors as targets for cancer radiotherapy.Tumor Targeting 1998; 3: 122–137.
Rogers BE, Douglas JT, Sosnowski BA, Ying W, Pierce G, Buchsbaum DJ, et al. Enhancedin vivo gene delivery to human ovarian cancer xenografts utilizing a tropismmodified adenovirus vector.Tumor Targeting 1998; 3: 25–31.
Rogers BE, McLean SF, Kirkman RL, Delia Manna D, Bright SJ, Olsen CC, et al.In vivo localization of [111In]-DTPA-D-Phe1-octreotide to human ovarian tumor xenografts induced to express the somatostatin receptor subtype 2 using an adenoviral vector.Clin Cancer Res 1999; 5: 383–393.
Zinn KR, Buchsbaum DJ, Chaudhuri TR, Mountz JM, Grizzle WE, Rogers BE. Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with99mTc or188Re.J Nucl Med 2000; 41: 887–895.
Zinn KR, Chaudhuri TR. The type 2 human somatostatin receptor as a platform for reporter gene imaging.Eur J Nucl Med 2002; 29: 388–399.
Hemminki A, Zinn KR, Liu B, Chaudhuri TR, Desmond RA, Rogers BE, et al.In vivo molecular chemotherapy and noninvasive imaging with an infectivity-enhanced adenovirus.J Natl Cancer Inst 2002; 94: 741–749.
Zinn KR, Chaudhuri TR, Krasnykh VN, Buchsbaum DJ, Belousova N, Grizzle WE, et al. Gamma camera dual imaging with a somatostatin receptor and thymidine kinase after gene transfer with a bicistronic adenovirus.Radiology 2002; 223: 417–425.
Rogers BE, Zinn KR, Lin C-Y, Chaudhuri TR, Buchsbaum DJ. Targeted radiotherapy with [90Y]-SMT 487 in mice bearing human nonsmall cell lung tumor xenografts induced to express human somatostatin receptor subtype 2 with an adenoviral vector.Cancer 2002; 94: 1298–1305.
Rogers BE, Zinn KR, Buchsbaum DJ. Gene transfer strategies for improving radiolabeled peptide imaging and therapy.Q J Nucl Med 2000; 44: 208–223.
Chaudhuri TR, Rogers BE, Buchsbaum DJ, Mountz JM, Zinn KR. A noninvasive reporter system to image adenovi-ral-mediated gene transfer to ovarian cancer xenografts.Gynecol Oncol 2001; 83: 432–438.
Freeman SM, Whartenby KA, Freeman JL, Abboud CN, Marrogi A.J. In situ use of suicide genes for cancer therapy.Semin Oncol 1996; 23: 31–45.
Morris JC. Enzyme/prodrug-based tumor vaccination: All politics (and immunity) are local.J Natl Cancer Inst 1999; 91: 1986–1989.
McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides.J Natl Cancer Inst 1996; 88: 1193–1203.
Danielson S, Kilstrup M, Barilla K, Jochimsen B, Neuhard J. Characterization of theEscherichia coli codBA operon encoding cytosine permease and cytosine deaminase.Mol Microbiol 1992; 6: 1335–1344.
Austin EA, Huber BE. A first step in the development of gene therapy for colorectal carcinoma: Cloning, sequencing, and expression ofEscherichia coli cytosine deaminase.Mol Pharmacol 1993; 43: 380–387.
Hamstra DA, Rice DJ, Pu A, Oyedijo D, Ross BD, Rehemtulla A. Combined radiation and enzyme/prodrug treatment for head and neck cancer in an orthotopic animal model.Radiation Res 1999; 152: 499–507.
Hamstra DA, Rice DJ, Fahmy S, Ross BD, Rehemtulla A. Enzyme/prodrug therapy for head and neck cancer using a catalytically superior cytosine deaminase.Hum Gene Ther 1999; 10: 1993–2003.
Huber BE, Austin EA, Good SS, Knick VC, Tibbels S, Richards CA.In vivo antitumor activity of 5-fluorocytosine on human colorectal carcinoma cells genetically modified to express cytosine deaminase.Cancer Res 1993; 53: 4619–4626.
Hirschowitz EA, Ohwada A, Pascal WR, Russi TJ, Crystal RG.In vivo adenovirus-mediated gene transfer of theEscherichia coli cytosine deaminase gene to human colon carcinoma-derived tumors induces chemosensitivity to 5-fluorocytosine.Hum Gene Ther 1995; 6: 1055–1063.
Mullen C. Metabolic suicide genes in gene therapy.Pharmacol Ther 1994; 63: 199–207.
Huber BE, Austin EA, Richards CA, Davis ST, Good SS. Metabolism of 5-fluorocytosine to 5-ftuorouracil in human colorectal tumor cells transduced with cytosine deaminase gene: Significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase.Proc Natl Acad Sci USA 1994; 91: 8302–8306.
Dong Y, Wen P, Manome Y, Parr M, Hirshowitz A, Chen L, et al.In vivo replication-deficient adenovirus vector- mediated transduction of the cytosine deaminase gene sen- sitizes glioma cells to 5-fiuorocytosine.Hum Gene Ther 1996; 7: 713–720.
DiMaio JM, Clary BM, Via DF, Coveney E, Pappas TN, Lyerly HK. Directed enzyme pro-drug gene therapy for pancreatic cancerin vivo.Surgery 1994; 116: 205–213.
Pederson LC, Buchsbaum DJ, Vickers SM, Kancharla SR, Mayo MS, Curiel DT, et al. Molecular chemotherapy combined with radiation therapy enhances killing of cholan-giocarcinoma cellsin vitro andin vivo.Cancer Res 1997; 57: 4325–4332.
Pederson LC, Vickers SM, Buchsbaum DJ, Kancharla SR, Mayo MS, Curiel DT, et al. Combining cytosine deaminase expression, 5-fluorocytosine exposure, and radiotherapy increases cytotoxicity to cholangiocarcinoma cells.J Gastrointest Surg 1998; 2: 283–291.
Stackhouse MA, Pederson LC, Grizzle WE, Curiel DT, Gebert J, Haack K, et al. Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models.Gene Ther 2000; 7: 1019–1026.
Miller CR, Williams CR, Buchsbaum DJ, Gillespie GY. Intratumoral 5-fluorouracil produced by cytosine deaminase/5-fluorocytosine gene therapy is effective for experimental human glioblastomas.Cancer Res 2002; 62: 773–780.
Ohwada A, Hirschowitz EA, Crystal RG. Regional delivery of an adenovirus vector containing theEscherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver.Hum Gene Ther 1996; 7: 1567–1576.
Hanna NN, Mauceri HJ, Wayne JD, Hallahan DE, Kufe DW, Weichselbaum RR. Virally directed cytosine deaminase/5-fiuorocytosine gene therapy enhances radiation response in human cancer xenografts.Cancer Res 1997; 57:: 4205–4209.
Chaudhuri TR, Krasnykh VN, Belousova N, Zinn KR, Buchsbaum DJ, Mountz JM, et al. An Ad-based strategy for imaging, radiotherapy, and enhanced tumor killing.Mol Ther 2001; 3: S25.
Buchsbaum DJ. Imaging and therapy of tumors induced to express somatostatin receptor by gene transfer using radiolabeled peptides and single chain antibody constructs.Semin Nucl Med 2004; 34: 32–46.
Liang Q, Gotts J, Satyamurthy N, Barrio J, Phelps ME, Gambhir SS, et al. Noninvasive, repetitive, quantitative measurement of gene expression from a bicistronic message by positron emission tomography, following gene transfer with adenovirus.Mol Ther 2002; 6: 73–82.
Tjuvajev JG, Doubrovin M, Akhurst T, Cai S, Balatoni J, Alauddin MM, et al. Comparison of radiolabeled nucleoside probes (FIAU, FHBG, and FHPG) for PET imaging of HSV1-tk gene expression.J Nucl Med 2002; 43: 1072–1083.
Blasberg RG. Molecular imaging and cancer.Mol Cancer Ther 2003; 2: 335–343.
Chung J-K. Sodium iodide symporter: Its role in nuclear medicine.J Nucl Med 2002; 43: 1188–1200.
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Buchsbaum, D.J., Chaudhuri, T.R., Yamamoto, M. et al. Gene expression imaging with radiolabeled peptides. Ann Nucl Med 18, 275–283 (2004). https://doi.org/10.1007/BF02984464
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DOI: https://doi.org/10.1007/BF02984464