Abstract
A major area of interest in nuclear medicine is the scintigraphic in vivo evaluation of complex cellular processes involved in tumour growth, progression and response to treatment with the aim of defining the biological properties that may orient clinicians towards different adjustments of therapy in individual patients. In the last decade, 99mTc-labelled lipophilic cations emerged as suitable tools to trace specific cellular processes and functions in a variety of malignant tumours, including breast cancer. Among these agents, 99mTc-methoxyisobutylisonitrile (MIBI) is the most widely evaluated tracer and may serve as a paradigm for this class of compounds. Many clinical studies have been performed to correlate 99mTc-MIBI uptake or clearance with histological, molecular and biochemical markers of various cellular processes, including apoptosis, proliferation, P-glycoprotein expression and neoangiogenesis. The final picture emerging from these studies is that the early tracer uptake reflects the mitochondrial status, which is affected by both apoptosis and proliferation, whereas the tracer clearance reflects the activity of drug transporters such as P-glycoprotein. On the basis of the imaging parameter chosen for the analysis of 99mTc-MIBI scan in breast cancer patients, the biological information provided may be related to different cellular processes that ultimately govern tumour response to treatment.
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References
Phelps ME. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A 2000; 97:9226–9233.
Blankenberg FG, Strauss HW. Nuclear medicine applications in molecular imaging. J Magn Reson Imaging 2002;16:352–361.
Sharma V, Luker GD, Piwnica-Worms D. Molecular imaging of gene expression and protein function in vivo with PET and SPECT. J Magn Reson Imaging 2002; 16:336–351.
Mariani G. Unexpected keys in cell biochemistry imaging: some lessons from technetium-99m-sestamibi. J Nucl Med 1996; 37:536–538.
Piwnica-Worms D, Kronauge JF, Chiu ML. Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence. Circulation 1990; 82:1826–1838.
Delmon-Moingeon LI, Piwnica-Worms D, Van den Abbeele AD, Holman BL, Davison A, Jones AG. Uptake of the cation hexakis(2-methoxyisobutylisonitrile)-technetium-99m by human carcinoma cell lines in vitro. Cancer Res 1990; 50:2198–2202.
Carvalho PA, Chiu ML, Kronauge JF, Kawamura M, Jones AG, Holman BL, Piwnica-Worms D. Subcellular distribution and analysis of technetium-99m-MIBI in isolated perfused rat hearts. J Nucl Med 1992; 33:1516–1522.
Crankshaw CL, Marmion M, Luker GD, Rao V, Dahlheimer J, Burleigh BD, Webb E, Deutsch KF, Piwnica-Worms D. Novel technetium (III)-Q complexes for functional imaging of multidrug resistance (MDR1) P-glycoprotein. J Nucl Med 1998; 39:77–86.
Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA, Croop JM. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res 1993; 53:977–984.
Gottesman, MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2:48–58.
Piwnica-Worms D, Rao VV, Kronauge JF, Croop JM. Characterization of multidrug resistance P-glycoprotein transport function with an organotechnetium cation. Biochemistry 1995; 34:12210–12220.
Ballinger JR, Bannerman J, Boxen I, Firby P, Hartman NG, Moore MJ. Technetium-99m-tetrofosmin as a substrate for P-glycoprotein: in vitro studies in multidrug-resistant breast tumor cells. J Nucl Med 1996; 37:1578–1582.
Ballinger JR, Muzzammil T, Moore MJ. Technetium-99m-furifosmin as an agent for functional imaging of multidrug resistance in tumors. J Nucl Med 1997; 38:1915–1919.
Hendrikse NH, Franssen EJ, van der Graaf WT, Vaalburg W, de Vries EG. Visualization of multidrug resistance in vivo. Eur J Nucl Med 1999; 26:283–293.
Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2:277–288.
Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol 2000; 10:369–377.
Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med 2000; 6:513–519.
Cory S, Adams JM. The bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2:647–656.
Ly JD, Grubb DR, Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis 2003; 8:115–128.
Del Vecchio S, Zannetti A, Aloj L, Caraco C, Ciarmiello A, Salvatore M. Inhibition of early99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma. Eur J Nucl Med Mol Imaging 2003; 30:879–887.
Aloj L, Zannetti A, Caraco C, Del Vecchio S, Salvatore M. Bcl-2 overexpression prevents99mTc-MIBI uptake in breast cancer cell lines. Eur J Nucl Med Mol Imaging 2004; 31:521–527.
Reed JC. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med 2001; 7:314–319.
Arun B, Kilic G, Yen C, Foster B, Yardley D, Gaynor R, Ashfaq R. Correlation of Bcl-2 and p53 expression in primary breast tumors and corresponding metastatic lymph nodes. Cancer 2003; 98:2554–2559.
Silvestrini R, Veneroni S, Daidone MG, Benini E, Boracchi P, Mezzetti M, Di Fronzo G, Rilke F, Veronesi U. The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst 1994; 86:499–504.
Gee JM, Robertson JF, Ellis IO, Willsher P, McClelland RA, Hoyle HB, Kyme SR, Finlay P, Blamey RW, Nicholson RI. Immunocytochemical localization of BCL-2 protein in human breast cancers and its relationship to a series of prognostic markers and response to endocrine therapy. Int J Cancer 1994; 59:619–628.
Sierra A, Castellsague X, Escobedo A, Lloveras B, Garcia-Ramirez M, Moreno A, Fabra A. Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: a pathway to metastatic progression in human breast cancer. Int J Cancer 2000; 89:142–147.
Chang J, Ormerod M, Powles TJ, Allred DC, Ashley SE, Dowsett M. Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma. Cancer 2000; 89:2145–2152.
Ziyaie D, Hupp TR, Thompson AM. P53 and breast cancer. Breast 2000; 9:239–246.
Ellis PA, Smith IE, Detre S, Burton SA, Salter J, A’Hern R, Walsh G, Johnston SR, Dowsett M. Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. Breast Cancer Res Treat 1998; 48:107–116.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997; 275:1129–1132.
Hirsch T, Marchetti P, Susin SA, Dallaporta B, Zamzami N, Marzo I, Geuskens M, Kroemer G. The apoptosis-necrosis paradox. Apoptogenic proteases activated after mitochondrial permeability transition determine the mode of cell death. Oncogene 1997; 15:1573–1581.
Marzo I, Brenner C, Zamzami N, JurgensmeierJM, Susin SA, Vieira HL, Prevost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 1998; 281:2027–2031.
Shimizu S, Eguchi Y, Kamiike W, Funahashi Y, Mignon A, Lacronique V, Matsuda H, Tsujimoto Y. Bcl-2 prevents apoptotic mitochondrial dysfunction by regulating proton flux. Proc Natl Acad Sci U S A 1998; 95:1455–1459.
Zhu X, Wu H, Xia J, Zhao M, Xianyu Z. The relationship between (99m)Tc-MIBI uptakes and tumor cell death/proliferation state under irradiation. Cancer Lett 2002; 182:217–222.
Vergote J, Di Benedetto M, Moretti JL, Azaloux H, Kouyoumdjian JC, Kraemer M, Crepin M. Could99mTc-MIBI be used to visualize the apoptotic MCF7 human breast cancer cells? Cell Mol Biol (Noisy-le-grand) 2001; 47:467–471.
Bom HS, Kim YC, Song HC, Min JJ, Kim JY, Park KO. Technetium-99m-MIBI uptake in small cell lung cancer. J Nucl Med 1998; 39:91–94.
Yamamoto Y, Nishiyama Y, Satoh K, Takashima H, Ohkawa M, Fujita J, Kishi T, Matsuno S, Tanabe M. Comparative study of technetium-99m-sestamibi and thallium-201 SPECT in predicting chemotherapeutic response in small cell lung cancer. J Nucl Med 1998; 39:1626–1629.
Yuksel M, Cermik F, Doganay L, Karlikaya C, Cakir E, Salan A, Berkarda S.99mTc-MIBI SPET in non-small cell lung cancer in relationship with Pgp and prognosis. Eur J Nucl Med Mol Imaging 2002; 29:876–881.
Nishiyama Y, Yamamoto Y, Satoh K, Ohkawa M, Kameyama K, Hayashi E, Fujita J, Tanabe M. Comparative study of Tc-99m MIBI and TI-201 SPECT in predicting chemotherapeutic response in non-small-cell lung cancer. Clin Nucl Med 2000; 25:364–369.
Dimitrakopoulou-Strauss A, Strauss LG, Goldschmidt H, Lorenz WJ, Maier-Borst W, van Kaick G. Evaluation of tumour metabolism and multidrug resistance in patients with treated malignant lymphomas. Eur J Nucl Med 1995; 22:434–442.
Kapucu LO, Akyuz C, Vural G, Oguz A, Atasever T, Buyukpamukcu M, Unlu M. Evaluation of therapy response in children with untreated malignant lymphomas using technetium-99m-sestamibi. J Nucl Med 1997; 38:243–247.
Cutrone JA, Yospur LS, Khalkhali I, Tolmos J, Devito A, Diggles L, Vargas MP, Shitabata P, French S. Immunohistologic assessment of technetium-99m-MIBI uptake in benign and malignant breast lesions. J Nucl Med 1998; 39:449–453.
Bonazzi G, Cistaro A, Bello M, Bessone M, Tetti M, Villata E, Coluccia C, Ardine M, Moz G, Massaioli N, Bisi G. Breast cancer cellular proliferation indexes and 99mTc-sesta Mibi capture: what correlation? J Exp Clin Cancer Res 2001; 20:91–94.
Nagamachi S, Jinnouchi S, Nabeshima K, Nishii R, Flores L 2nd, Kodama T, Kawai K, Tamura S, Yokogami K, Samejima T, Wakisaka S. The correlation between99mTc-MIBI uptake and MIB-1 as a nuclear proliferation marker in glioma—a comparative study with 201Tl. Neuroradiology 2001; 43:1023–1030.
Ak I, Gulbas Z, Altinel F, Vardareli E. Tc-99m MIBI uptake and its relation to the proliferative potential of brain tumors. Clin Nucl Med 2003; 28:29–33.
Evan G, Littlewood T. A matter of life and cell death. Science 1998; 281:1317–1322.
Kanazawa S, Soucek L, Evan G, Okamoto T, Peterlin BM. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis. Oncogene 2003; 22:5707–5711.
Iaccarino I, Hancock D, Evan G, Downward J. c-Myc induces cytochrome c release in Rat1 fibroblasts by increasing outer mitochondrial membrane permeability in a Bid-dependent manner. Cell Death Differ 2003; 10:599–608.
Pelengaris S, Khan M, Evan G. c-MYC: more than just a matter of life and death. Nat Rev Cancer 2002; 2:764–776.
Guo Z, Yikang S, Yoshida H, Mak TW, Zacksenhaus E. Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis. Cancer Res 2001; 61:8395–8400.
Hickman ES, Moroni MC, Helin K. The role of p53 and pRB in apoptosis and cancer. Curr Opin Genet Dev 2002; 12:60–66.
Hsieh JK, Fredersdorf S, Kouzarides T, Martin K, Lu X. E2F1-induced apoptosis requires DNA binding but not transactivation and is inhibited by the retinoblastoma protein through direct interaction. Genes Dev 1997; 11:1840–1852.
Moroni MC, Hickman ES, Denchi EL, Caprara G, Colli E, Cecconi F, Muller H, Helin K. Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 2001; 3:552–558.
Furukawa Y, Nishimura N, Satoh M, Endo H, Iwase S, Yamada H, Matsuda M, Kano Y, Nakamura M. Apaf-1 is a mediator of E2F-1-induced apoptosis. J Biol Chem 2002; 277:39760–39768.
de Jong JS, van Diest PJ, Baak JP. Number of apoptotic cells as a prognostic marker in invasive breast cancer. Br J Cancer 2000; 82:368–373.
Archer CD, Parton M, Smith IE, Ellis PA, Salter J, Ashley S, Gui G, Sacks N, Ebbs SR, Allum W, Nasiri N, Dowsett M. Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer. Br J Cancer 2003; 89:1035–1041.
List AF. Non-P-glycoprotein drug export mechanisms of multidrug resistance. Semin Hematol 1997; 34:20–24.
Trock BJ, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 1997; 89:917–931.
Moretti JL, Azaloux H, Boisseron D, Kouyoumdjian JC, Vilcoq J. Primary breast cancer imaging with technetium-99m sestamibi and its relation with P-glycoprotein overexpression. Eur J Nucl Med 1996; 23:980–986.
Kostakoglu L, Elahi N, Kiratli P, Ruacan S, Sayek I, Baltali E, Sungur A, Hayran M, Bekdik CF. Clinical validation of the influence of P-glycoprotein on technetium-99m-sestamibi uptake in malignant tumors. J Nucl Med 1997; 38:1003–1008.
Sun SS, Hsieh JF, Tsai SC, Ho YJ, Lee JK, Kao CH. Expression of mediated P-glycoprotein multidrug resistance related to Tc-99m MIBI scintimammography results. Cancer Lett 2000; 153:95–100.
Kao CH, Tsai SC, Liu TJ, Ho YJ, Wang JJ, Ho ST, ChangLai SP. P-glycoprotein and multidrug resistance-related protein expressions in relation to technetium-99m methoxyisobutylisonitrile scintimammography findings. Cancer Res 2001; 61:1412–1414.
Del Vecchio S, Ciarmiello A, Potena MI, Carriero MV, Mainolfi C, Botti G, Thomas R, Cerra M, D’Aiuto G, Tsuruo T, Salvatore M. In vivo detection of multidrug-resistant (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients. Eur J Nucl Med 1997; 24:150–159.
Ciarmiello A, Del Vecchio S, Silvestro P, Potena MI, Carriero MV, Thomas R, Botti G, D’Aiuto G, Salvatore M. Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer. J Clin Oncol 1998; 16:1677–1683.
Sciuto R, Pasqualoni R, Bergomi S, Petrilli G, Vici P, Belli F, Botti C, Mottolese M, Maini CL. Prognostic value of99mTc-sestamibi washout in predicting response of locally advanced breast cancer to neoadjuvant chemotherapy. J Nucl Med 2002; 43:745–751.
Fujii H, Nakamura K, Kubo A, Enomoto K, Ikeda T, Kubota T, Matsuzaki SW, Kitajima M. Preoperative evaluation of the chemosensitivity of breast cancer by means of double phase99mTc-MIBI scintimammography. Ann Nucl Med 1998; 12:307–312.
Takamura Y, Miyoshi Y, Taguchi T, Noguchi S. Prediction of chemotherapeutic response by technetium 99m MIBI scintigraphy in breast carcinoma patients. Cancer 2001; 92:232–239.
Mubashar M, Harrington KJ, Chaudhary KS, Lalani el-N, Stamp GW, Sinnett D, Glass DM, Peters AM.99mTc-sestamibi imaging in the assessment of toremifene as a modulator of multidrug resistance in patients with breast cancer. J Nucl Med 2002; 43:519–525.
Warri AM, Huovinen RL, Laine AM, Martikainen PM, Harkonen PL. Apoptosis in toremifene-induced growth inhibition of human breast cancer cells in vivo and in vitro. J Natl Cancer Inst 1993; 85:1412–1418.
Cayre A, Cachin F, Maublant J, Mestas D, Feillel V, Ferriere JP, Kwiaktowski F, Chevillard S, Finat-Duclos F, Verrelle P, Penault-Llorca F. Single static view99mTc-sestamibi scintimammography predicts response to neoadjuvant chemotherapy and is related to MDR expression. Int J Oncol 2002; 20:1049–1055.
Fuster D, Munoz M, Pavia J, Palacin A, Bellet N, Mateos JJ, Martin F, Ortega M, Setoain FJ, Pons F. Quantified99mTc-MIBI scintigraphy for predicting chemotherapy response in breast cancer patients: factors that influence the level of 99mTc-MIBI uptake. Nucl Med Commun 2002; 23:31–38.
Kim R, Osaki A, Hirai T, Toge T. Utility of technetium-99m methoxyisobutyl isonitrile uptake analysis for prediction of the response to chemotherapy in advanced and relapsed breast cancer. Breast Cancer 2002; 9:240–247.
Mankoff DA, Dunnwald LK, Gralow JR, Ellis GK, Schubert EK, Charlop AW, Tseng J, Rinn KJ, Livingston RB. [Tc-99m]-sestamibi uptake and washout in locally advanced breast cancer are correlated with tumor blood flow. Nucl Med Biol 2002; 29:719–727.
Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med 1991; 324:1–8.
Boudreau N, Myers C. Breast cancer-induced angiogenesis: multiple mechanisms and the role of the microenvironment. Breast Cancer Res 2003; 5:140–146.
Yoon JH, Bom HS, Song HC, Lee JH, Jaegal YJ. Double-phase Tc-99m sestamibi scintimammography to assess angiogenesis and P-glycoprotein expression in patients with untreated breast cancer. Clin Nucl Med 1999; 24:314–318.
Scopinaro F, Schillaci O, Scarpini M, Mingazzini PL, Di Macio L, Banci M, Danieli R, Zerilli M, Limiti MR, Centi Colella A. Technetium-99m sestamibi: an indicator of breast cancer invasiveness. Eur J Nucl Med 1994; 21:984–987.
Kim SW, Park SS, Ahn SJ, Chung KW, Moon WK, Im JG, Yeo JS, Chung JK, Noh DY. Identification of angiogenesis in primary breast carcinoma according to the image analysis. Breast Cancer Res Treat 2002; 74:121–129.
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108:153–164.
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The authors thank all of their collaborators who have contributed to these studies. This work was supported by Associazione Italiana Ricerca Cancro (AIRC) and FIRB-MIUR.
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Del Vecchio, S., Salvatore, M. 99mTc-MIBI in the evaluation of breast cancer biology. Eur J Nucl Med Mol Imaging 31 (Suppl 1), S88–S96 (2004). https://doi.org/10.1007/s00259-004-1530-0
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DOI: https://doi.org/10.1007/s00259-004-1530-0