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Use of Positron Emission Tomography in Anticancer Drug Development

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Abstract

Positron emission tomography (PET) is increasingly being used in anticancer drug development. The technique is applicable to studies of drug delivery, and where specific probes are available, to provide pharmacodynamic readouts noninvasively in patients. Mathematical modeling of the imaging data enhances the quality of information that is obtained from such studies. This section provides a review of the PET methodologies that have been used for the development of new cancer therapies. Other than imaging of radiolabeled drugs, PET modeling has found extensive application in studies with 2-[11C]thymidine, [18F]fluorodeoxyglucose, H2 15O, C15O, and receptor ligands.

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References

  1. Huang SC, Phelps ME: Principles of tracer kinetic modeling in positron tomography and autoradiography. In: Phelps ME, Mazziota JC, Schelbert HR (eds) Positron Emission Tomography and Autoradiography: Principles and Applications for the Brain and Heart, Raven Press, New York, 1986, pp 287–346

    Google Scholar 

  2. Cunningham VJ, Jones T: Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab 13(1): 15–23, 1993

    Google Scholar 

  3. Patlak CS, Blasberg RG, Fenstermacher JD: Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3(1): 1–7, 1983

    Google Scholar 

  4. Kissel J, Brix G, Bellemann ME, Strauss LG, Dimitrakopoulou-Strauss A, Port R, Haberkorn U, Lorenz WJ: Pharmacokinetic analysis of 5–[18F]fluorouracil tissue concentrations measured with positron emission tomography in patients with liver metastases from colorectal adenocarcinoma. Cancer Res 57(16): 3415–3423, 1997

    Google Scholar 

  5. Presant CA, Wolf W, Albright MJ, Servis KL, Ring Rd, Atkinson D, Ong RL, Wiseman C, King M, Blayney D, et al.: Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics. J Clin Oncol 8(11): 1868–1873, 1990

    Google Scholar 

  6. Presant CA, Wolf W, Waluch V, Wiseman C, Kennedy P, Blayney D, Brechner RR: Association of intratumoral pharmacokinetics of fluorouracil with clinical response [see comments]. Lancet 343(8907): 1184–1187, 1994

    Google Scholar 

  7. Pinedo HM, Peters GF: Fluorouracil: biochemistry and pharmacology. J Clin Oncol 6(10): 1653–1664, 1988

    Google Scholar 

  8. Saleem A, Yap J, Osman S, Brady F, Suttle B, Lucas SV, Jones T, Price PM, Aboagye EO: Modulation of fluorouracil tissue pharmacokinetics by eniluracil: in-vivo imaging of drug action. Lancet 355(9221): 2125–2131, 2000

    Google Scholar 

  9. Aboagye EO, Saleem A, Cunningham V, Osman S, Price P: Extraction of 5–fluorouracil by tumor and liver: a non-invasive positron emission tomography study of patients with gastrointestinal cancer. Cancer Res 61: 4937–4941, 2001

    Google Scholar 

  10. Saleem A, Harte RJ, Matthews JC, Osman S, Brown GD, Bleehen N, Connors T, Jones T, Price PM, Aboagye EO: Pharmacokinetic evaluation of N-[2–(Dimethylamino)ethyl] acridine-4–carboxamide (DACA; XR5000) in patients by positron emission tomography. J Clin Oncol 19: 1421–1429, 2001

    Google Scholar 

  11. Meikle SR, Matthews JC, Brock CS, Wells P, Harte RJ, Cunningham VJ, Jones T, Price P: Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study. Cancer Chemother Pharmacol 42(3): 183–193, 1998

    Google Scholar 

  12. Gunn RN, Yap JT, Wells P, Osman S, Price P, Jones T, Cunningham VJ: A general method to correct PET data for tissue metabolites using a dual-scan approach. J Nucl Med 41(4): 706–711, 2000

    Google Scholar 

  13. Mankoff DA, Shields AF, Graham MM, Link JM, Eary JF, Krohn KA: Kinetic analysis of 2–[carbon-11]thymidine PET imaging studies: compartmental model and mathematical analysis. J Nucl Med 39: 1043–1055, 1998

    Google Scholar 

  14. Eary JF, Mankoff DA, Spence AM, Berger MS, Olshen A, Link JM, O'Sullivan F, Krohn KA: 2–[C-11]thymidine imaging of malignant brain tumors. Cancer Res 59: 615–621, 1999

    Google Scholar 

  15. Wells P, Gunn R, Steel C, Alison M, Jones T, Price P: Measurement of cell proliferation in vivo using [2–11C]thymidine. Proc Am Soc Clin Oncol 16: 548a, 1997

    Google Scholar 

  16. Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, Kozawa SM, Zheng M, Lewellen B, Lewellen TK, Grierson JR, Krohn KA: Carbon-11–thymidine and FDG to measure therapy response. J Nucl Med 39: 1757–1762, 1998

    Google Scholar 

  17. Blasberg RG, Roelcke U, Weinreich R, Beattie B, von Ammon K, Yonekawa Y, Landolt H, Guenther I, Crompton NEA, Vontobel P, Missimer J, Maguire RP, Koziorowski J, Knust EJ, Finn RD, Leendrs KL: Imaging brain tumor proliferative activity with [124I]iododeoxyuridine. Cancer Res 60: 624–635, 2000

    Google Scholar 

  18. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, Muzik O, Mangner TJ: Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4: 1334–1336, 1998

    Google Scholar 

  19. Mankoff DA, Shields AF, Graham MM, Link JM, Krohn KA: A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labelled metabolites. J Nucl Med 37: 2049–2057, 1996

    Google Scholar 

  20. Warburg O, Wind F, Neglers E: On the metabolism of tumours. In: Warburg O (ed.) Metabolism of Tumours, Arnold Constable, London, 1930, pp 254–270

    Google Scholar 

  21. Firth JD, Ebert BL, Ratcliffe PJ: Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270: 21021–21027, 1995

    Google Scholar 

  22. Riddle SR, Ahmad A, Ahmad S, Deeb SS, Malkki M, Schneider BK, Allen CB, White CW: Hypoxia induces hexokinase II gene expression in human lung cell line A549. Am J Physiol Lung Cell Mol Physiol 278: L407–L416, 2000

    Google Scholar 

  23. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A: Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271: 32529–32537, 1996

    Google Scholar 

  24. Dang CV, Semenza G: Oncogenic alterations of metabolism. Trends Biochem Sci 24: 68–72, 1999

    Google Scholar 

  25. Weber G: Carbohydrate metabolism in cancer cells and the molecular correlation concept. Naturwissenschaften 9: 418–429, 1968

    Google Scholar 

  26. Weber G: Enzymology of cancer cells (first of two parts). N Engl J Med 296(9): 486–492, 1977

    Google Scholar 

  27. Aloj L, Carac'o C, Jagoda E, Eckelman WC, Neumann RD: Glut-1 and hexokinase expression: relationship with 2–fluoro-2–deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res 59: 4709–4714, 1999

    Google Scholar 

  28. Chung JK, Lee YJ, Kim C, Choi SR, Kim M, Lee K, Jeong JM, Lee DS, Jang JJ, Lee MC: Mechanisms related to [18F]fluorodeoxyglucose uptake of human colon cancers transplanted in nude mice. J Nucl Med 40: 339–346, 1999

    Google Scholar 

  29. Sokoloff L, Reivich M, Kennedy C, Des-Rosiers MH, Patlak CSW, Pettigrew KD, Sakurada O, Shinohara M: The [14C]deoxyglucose method for the measurement of local cerebral glucose utilisation: theory, procedure and normal values in the conscious and anaesthetized albino rat. J Neurochem 28: 897–916, 1997

    Google Scholar 

  30. Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE: Tomographic measurement of local cerebral glucose metabolic rate in humans with 18F-fluoro-2–deoxy-D-glucose: validation of method. Ann Neurol 6: 371–388, 1979

    Google Scholar 

  31. Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, Pruim J, Price P: Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer 35: 1773–1782, 1999

    Google Scholar 

  32. Wu H, Dimitrakopoulou-Strauss A, Heichel TO, Lehner B, Bernd L, Ewerbeck V, Bruger C, Strauss LG: Quantitative evaluation of skeletal tumours with dynamic FDG PET: SUV in comparison to Patlak analysis. Eur J Nucl Med 28: 704–710, 2001

    Google Scholar 

  33. Spence AM, Muzi M, Graham MM, O'Sullivan F, Krohn KA, Link JM, Lewellen TK, Freeman SD, Berger MS, Ojemann GA: Glucose metabolism in human malignant gliomas measured quantitatively with PET, 1[C-11]Glucose and FDG: analysis of the FDG lumped constant. J Nucl Med 39: 440–448, 1998

    Google Scholar 

  34. Brock CS, Meikle SR, Price P: Does fluorine-18 fluorodeoxyglucose metabolic imaging of tumours benefit oncology? Eur J Nucl Med 24(6): 691–705, 1997

    Google Scholar 

  35. Brock CS, Young H, O'Reilly SM, Matthews J, Osman S, Evans H, Newlands ES, Price P: Early evaluation of tumour metabolic response using [18F]fluorodeoxyglucose and positron emission tomography: a pilot study following the phase II chemotherapy schedule for temozolomide in recurrent high-grade gliomas. Br J Cancer 82: 608–615, 2000

    Google Scholar 

  36. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R: Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol 11: 2101–2111, 1993

    Google Scholar 

  37. Maisey NR, Webb A, Flux GD, Padhani A, Cunningham DC, Ott RJ: FDG-PET in the prediction of survival of patients with cancer of the pancreas: a pilot study. Br J Cancer 83: 287–293, 2000

    Google Scholar 

  38. Findlay M, Young H, Cunningham D, Iveson A, Cronin B, Hickish T, Pratt B, Husband J, Flower M, Ott R: Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil [see comments]. J Clin Oncol 14(3): 700–708, 1996

    Google Scholar 

  39. Ogawa T, Uemura K, Shishido F, Yamaguchi T, Murakami M, Inugami A, Kanno I, Sasaki H, Kato T, Hirata K, et al.: Changes of cerebral blood flow, and oxygen and glucose metabolism following radiochemotherapy of gliomas: a PET study. J Comput Assist Tomogr 12(2): 290–297, 1988

    Google Scholar 

  40. Wilson CB, Lammertsma AA, McKenzie CG, Sikora K, Jones T: Measurements of blood flow and exchanging water space in breast tumors using positron emission tomography: a rapid and noninvasive dynamic method. Cancer Res 52(6): 1592–1597, 1992

    Google Scholar 

  41. Ziegler SI, Haberkorn U, Byrne H, Tong C, Schosser R, Krieter H, Kaja S, Richolt JA, Lammertsma AA, Price P: Measurement of liver blood flow using oxygen-15 labelled water and dynamic positron emission tomography: limitations of model description. Eur J Nucl Med 23: 169–177, 1996

    Google Scholar 

  42. Anderson H, Yap JT, Price P: Measurement of tumour and normal tissue (NT) perfusion by positron emission tomography (PET) in the evaluation of antivascular therapy: results in the phase I study of combretastatin A4 phosphate (CA4P). Proc Am Soc Clin Oncol 19: 179a, 2000

    Google Scholar 

  43. Yap JT, Rhodes CG, Cunningham VJ, Jones T, Anderson H, Price PM: Measurement of cardiac output during PET tumor blood flow studies. Proc Soc Nucl Med 2000

  44. Tozer GM, Prise VE, Wilson J, Locke RJ, Vojnovic B, Stratford MRL, Dennis MF, Chaplin DJ: Combretastatin A-4 phosphate as a tumor vascular-targeting agent: early effects in tumors and normal tissues. Cancer Res 59: 1626–1634, 1999

    Google Scholar 

  45. McGuire AH, Dehdashti F, Siegel BA, Lyss AP, Brodack JW, Mathias CJ, Mintun MA, Katzenellenbogen JA, Welch MJ: Positron tomographic assessment of 16 alpha-[18F] fluoro-17–beta-estradiol uptake in metastatic breast carcinoma. J Nucl Med 32(8): 1526–1531, 1991

    Google Scholar 

  46. Dehdashti F, Flanagan FL, Mortimer JE, Katzenellenbogen JA, Welch MJ, Siegel BA: Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. Eur J Nucl Med 26(1): 51–56, 1999

    Google Scholar 

  47. Godfrey K: Compartmental Models and Their Applications. Academic Press, London, 1983

    Google Scholar 

  48. Cunningham VJ, Lammertsma AA: Radioligand studies in brain: kinetic analysis of PET data. Med Chem Res 5: 79–96, 1995

    Google Scholar 

  49. Patlak CS, Blasberg RG: Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5: 584–590, 1985

    Google Scholar 

  50. Logan J, Fowler JS, Volkow ND, AP W, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ: Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10: 740–747, 1990

    Google Scholar 

  51. Anzai Y, Minoshima S, Wolf GT, Wahl RL: Head and neck cancer: detection of recurrence with three-dimensional principal components analysis at dynamic FDG PET. Radiology 212: 285–290, 1999

    Google Scholar 

  52. Dimitrakopoulou-Strauss A, Strauss LG, Schlag P, Hohenberger P, Irngartinger G, Oberdorfer F, Doll Jvan Kaick G: Intravenous and intra-arterial oxygen-15–labeled water and fluorine-18–labeled fluorouracil in patients with liver metastases from colorectal carcinoma. J Nucl Med 39(3): 465–473, 1998

    Google Scholar 

  53. Gunn RN, Lammertsma AA, Cunningham VJ: Parametric imaging of ligand-receptor interactions using a reference tissue model and cluster analysis. In: Carson RE, Daube-Witherspoon ME, Herscovitch P (eds) Quantitative Function Brain Imaging with Positron Emission Tomography, Academic Press, London, 1998, pp 401–406

    Google Scholar 

  54. Carson RE, Huang S-C, Phelps ME: Error analysis of the integrated projection technique and the weighted integration method for measurement of local cerebral blood flow with positron emission tomography. J Nucl Med 25: P88, 1984

    Google Scholar 

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Authors and Affiliations

  1. PET Oncology Group, Department of Cancer Medicine, Imperial College of Science, Technology and Medicine, Faculty of Medicine, Department of Cancer Medicine, London, UK

    Eric O. Aboagye & Patricia M. Price

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  1. Eric O. Aboagye
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  2. Patricia M. Price
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Aboagye, E.O., Price, P.M. Use of Positron Emission Tomography in Anticancer Drug Development. Invest New Drugs 21, 169–181 (2003). https://doi.org/10.1023/A:1023521412787

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