Repopulation of cancer cells during therapy: An important cause of treatment failure

Nature Reviews Cancer

Volumn 5, Issue 7, 2005, Pages 516-525

  Kim, John J ^a   Tannock, Ian F ^b  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BROXURIDINE; CD31 ANTIGEN; CELL DNA; CETUXIMAB; CYCLIN D1; CYTOSTATIC AGENT; CYTOTOXIC AGENT; DOCETAXEL; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; FLUOROURACIL; GEMCITABINE; GROWTH FACTOR; KI 67 ANTIGEN; METHOTREXATE; MITOGEN ACTIVATED PROTEIN KINASE; PIMONIDAZOLE; PLATINUM DERIVATIVE; RAPAMYCIN DERIVATIVE; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; TEMSIROLIMUS;

CANCER ADJUVANT THERAPY; CANCER CELL; CANCER CHEMOTHERAPY; CANCER CONTROL; CANCER GROWTH; CANCER HORMONE THERAPY; CANCER MODEL; CANCER RADIOTHERAPY; CANCER SURVIVAL; CELL CYCLE; CELL DEATH; CELL DIFFERENTIATION; CELL POPULATION; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL PROTOCOL; CLINICAL TRIAL; COLONY FORMING CELL; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG SENSITIVITY; FLOW CYTOMETRY; HUMAN; HYPOXIC CELL; INTENSITY MODULATED RADIATION THERAPY; MATHEMATICAL MODEL; META ANALYSIS; MITOSIS RATE; NONHUMAN; OUTCOMES RESEARCH; PRIORITY JOURNAL; RADIATION DOSE; RADIATION DOSE FRACTIONATION; RADIATION INJURY; RADIOSENSITIZATION; REVIEW; SURVIVAL RATE; SYSTEMATIC REVIEW; TREATMENT FAILURE; TUMOR BLOOD FLOW;

ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; CELL SURVIVAL; DISEASE PROGRESSION; DOSE FRACTIONATION; DRUG ADMINISTRATION SCHEDULE; HUMANS; NEOPLASMS; RADIOTHERAPY; TREATMENT FAILURE;

EID: 21744437791     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1650     Document Type: Review

References (101)

1. Kummermehr, J. C. Tumour stem cells - the evidence and the ambiguity. Acta Oncol. 40, 981-988 (2001).
2. Withers, H. R., Taylor, J. M. & Maciejewski, B. The hazard of accelerated tumour clonogen repopulation during radiotherapy. Acta Oncol. 27, 131-146 (1988). This paper demonstrated reduced local control of head and neck cancer using radiotherapy with increase in overall treatment time; it was the first paper to demonstrate the clinical significance of accelerated repopulation.
3. Malaise, E. & Tubiana, M. Growth of the cells of an experimental irradiated fibrosarcoma in the C3H mouse. Hebd. Seances Acad Sci., Ser. D, Sci. Nat. 263, 292-295 (1966) (in French).
4. Szczepanski, L. & Trott, K. R. Post-irradiation proliferation kinetics of a serially transplanted murine adenocarcinoma. Br. J. Radiol. 48, 200-208 (1975).
5. Jung, H., Kruger, H. J., Brammer, I., Zywietz, F. & Beck-Bornholdt, H. P. Cell population kinetics of the rhabdomyosarcoma R1H of the rat after single doses of X-rays. Int. J. Radiat. Biol. 57, 567-589 (1990).
6. Beck-Bornholdt, H. P., Omniczynski, M., Theis, E., Vogler, H. & Wurschmidt, F. Influence of treatment time on the response of rat rhabdomyosarcoma R1H to fractionated irradiation. Acta Oncol. 30, 57-63 (1991).
7. Raabe, A. et al. Influence of dose per fraction and overall treatment time on the response of pulmonary micrometastases of the R1H-tumour to fractionated irradiation. Radiother. Oncol. 56, 259-264 (2000).
8. Beck-Bornholdt, H. P. Should tumours be clamped in radiobiological fractionation experiments? Int. J. Radiat. Oncol. Biol. Phys. 21, 675-682 (1991).
9. 50 as a measure of clonogen doubling time in irradiated and unirradiated tumours. Int. J. Radiat. Oncol. Biol. Phys. 21, 1195-1202 (1991).
10. Begg, A. C., Hofland, I. & Kummermehr, J. Tumour cell repopulation during fractionated radiotherapy: correlation between flow cytometric and radiobiological data in three murine tumours. Eur. J. Cancer 27, 537-543 (1991).
11. Speke, A. K. & Hill, R. P. Repopulation kinetics during fractionated irradiation and the relationship to the potential doubling time, Tpot. Int. J. Radiat. Oncol. Biol. Phys. 31, 847-856 (1995).
12. Suit, H. D., Howes, A. E. & Hunter, N. Dependence of response of a C3H mammary carcinoma to fractionated irradiation on fractionation number and intertreatment interval. Radiat. Res. 72, 440-454 (1977).
13. Petersen, C. et al. Repopulation of FaDu human squamous cell carcinoma during fractionated radiotherapy correlates with reoxygenation. Int. J. Radiat. Oncol. Biol. Phys. 51, 483-493 (2001).
14. Speke, A. K. & Hill, R. P. The effects of clamping and reoxygenation on repopulation during fractionated irradiation. Int. J. Radiat. Oncol. Biol. Phys. 31, 857-863 (1995).
15. Hessel, F. et al. Repopulation of moderately well-differentiated and keratinizing GL human squamous cell carcinomas growing in nude mice. Int. J. Radiat. Oncol. Biol. Phys. 58, 510-518 (2004).
16. Allam, A. et al. The effect of the overall treatment time of fractionated irradiation on the tumour control probability of a human soft tissue sarcoma xenograft in nude mice. Int J. Radiat. Oncol. Biol. Phys. 32, 105-111 (1995).
17. Sham, E. & Durand, R. E. Cell kinetics and repopulation parameters of irradiated xenograft tumours in SCID mice: comparison of two dose-fractionation regimens. Eur. J. Cancer 35, 850-858 (1999).
18. Rofstad, E. K. Repopulation between radiation fractions in human melanoma xenografts. Int. J. Radiat. Oncol. Biol. Phys. 23, 63-68 (1992).
19. Bentzen, S. M. & Thames, H. D. Clinical evidence for tumour clonogen regeneration: interpretations of the data. Radiother. Oncol. 22, 161-166 (1991).
20. Withers, H. R. et al. Local control of carcinoma of the tonsil by radiation therapy: an analysis of patterns of fractionation in nine institutions. Int. J. Radiat. Oncol. Biol. Phys. 33, 549-562 (1995).
21. Begg, A. C. et al. The predictive value of cell kinetic measurements in a European trial of accelerated fractionation in advanced head and neck tumours: an interim report. Int. J. Radiat. Oncol. Biol. Phys. 19, 1449-1453 (1990).
22. Maciejewski, B. & Majewski, S. Dose fractionation and tumour repopulation in radiotherapy for bladder cancer. Radiother. Oncol. 21, 163-170 (1991).
23. Barton, M. B., Keane, T. J., Gadalla, T. & Maki, E. The effect of treatment time and treatment interruption on tumour control following radical radiotherapy of laryngeal cancer. Radiother. Oncol. 23, 137-143 (1992).
24. Fyles, A., Keane, T. J., Barton, M. & Simm, J. The effect of treatment duration in the local control of cervix cancer. Radiother. Oncol. 25, 273-279 (1992).
25. Tarnawski, R. et al. How fast is repopulation of tumour cells during the treatment gap? Int J. Radiat. Oncol. Biol. Phys. 54, 229-236 (2002).
26. Withers, H. R. & Peters, L. J. Transmutability of dose and time. Commentary on the first report of RTOG 90003 (K. K. FU et al). Int. J. Radiat. Oncol. Biol. Phys. 48, 1-2 (2000).
27. Fu, K. K. et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int. J. Radiat. Oncol. Biol. Phys. 48, 7-16 (2000). A report of a large randomized clinical trial that demonstrated improved locoregional control of head and neck squamous cell carcinomas with radiotherapy delivered by accelerated fractionation compared with conventional fractionation.
28. Suwinski, R. et al. Time factor in postoperative radiotherapy: a multivariate locoregional control analysis in 868 patients. Int. J. Radiat. Oncol. Biol. Phys. 56, 399-412 (2003).
29. Stephens, T. C. & Peacock, J. H. Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. Br. J. Cancer 36, 313-321 (1977).
30. Rosenblum, M. L., Knebel, K. D., Vasquez, D. A. & Wilson, C. B. In vivo clonogenic tumour cell kinetics following 1,3-bis(2-chloroethyl)-1- nitrosourea brain tumour therapy. Cancer Res. 36, 3718-3725 (1976).
31. Rosenblum, M. L., Gerosa, M. A., Dougherty, D. V. & Wilson, C. B. Improved treatment of a brain-tumour model. Part 1: Advantages of single- over muitiple-dose BCNU schedules. J. Neurosurg. 58, 177-182 (1983).
32. Milas, L. et al. Dynamics of tumour cell clonogen repopulation in a murine sarcoma treated with cyclophosphamide. Radiother. Oncol. 30, 247-253 (1994).
33. Wu, L. & Tannock, I. F. Repopulation in murine breast tumours during and after sequential treatments with cyclophosphamide and 5-fluorpuracil. Cancer Res. 63, 2134-2138 (2003).
34. Durand, R. E. & Vanderbyl, S. L. Tumour resistance to therapy: a genetic or kinetic problem? Cancer Commun. 1, 277-283 (1989).
35. Durand, R. E. Multicell spheroids as a model for cell kinetic studies. Cell Tissue Kinet. 23, 141-159 (1990).
36. Bourhis, J. et al. Rapid tumour cell proliferation after induction chemotherapy in propharyngeal cancer. Laryngoscope 104, 468-472 (1994).
37. Davis, A. J., Chapman, W., Hedley, D. W., Oza, A. M. & Tannock, I. F. Assessment of tumour cell repopulation after chemotherapy for advanced ovarian cancer: pilot study. Geometry A 51, 1-6 (2003).
38. Steel, G. G. Growth Kinetics of Tumours: Cell Population Kinetics in Relation to the Growth and Treatment of Cancer (Clarendon, Oxford, 1977).
39. Tannock, I. F. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br. J. Cancer 22, 258-273 (1968).
40. Tannock, I. F. Population kinetics of carcinoma cells, capillary endothelial cells, and fibroblasts in a transplanted mouse mammary tumour. Cancer Res. 30, 2470-2476 (1970).
41. Hirst, D. G., Denekamp, J. & Hobson, B. Proliferation kinetics of endothelial and tumour cells in three mouse mammary carcinomas. Cell Tissue Kinet. 15, 251-261 (1982).
42. Fowler, J. F. Rapid repopulation in radiotherapy: a debate on mechanism. The phantom of tumour treatment - continually rapid proliferation unmasked. Radiother. Oncol 22, 156-158 (1991).
43. Kummermehr, J. & Trott, K. R. in Stem cells (ed. Potten, C. S.) 363-399 (Academic, London, 1997).
44. Dorr, W. Three A's of repopulation during fractionated irradiation of squamous epithelia: asymmetry loss, acceleration of stem-cell divisions and abortive divisions. Int. J. Radiat. Biol. 72, 635-643 (1997).
45. Denekamp, J. The change in the rate of repopulation during multifraction irradiation of mouse skin. Br. J. Radiol. 45, 801 (1972).
46. Denekamp, J. Changes in the rate of repopulation during multifraction irradiation of mouse skin. Br. J. Radiol. 46, 381-387 (1973).
47. Petersen, C. et al. Proliferation and micromilieu during fractionated irradiation of human FaDu squamous cell carcinoma in nude mice. Int. J. Radiat. Biol. 79, 469-477 (2003).
48. Balaban, N. et al. The effect of ionizing radiation on signal transduction: antibodies to EGF receptor sensitive A431 cells to radiation. Biochim. Biophys. Acta 1314, 147-156 (1996).
49. Schmidt-Ullrich, R. K. et al. Molecular mechanisms of radiation-induced accelerated repopulation. Radiat. Oncol. Investig. 7, 321-330 (1999).
50. Carter, S. et al. Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells. Oncogene 16, 2787-2796 (1998).
51. Kavanagh, B. D., Dent, P., Schmidt-Ullrich, R. K., Chen, P. & Mikkelsen, R. B. Calcium-dependent stimulation of mitogen-activated protein kinase activity in A431 cells by low doses of ionizing radiation. Radiat. Res. 149, 579-587 (1998).
52. Bowers, G. et al. The relative role of ErbB1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells. Oncogene 20, 1388-1397 (2001).
53. Schmidt-Ullrich, R. K. et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15, 1191-1197 (1997). This study demonstrated that radiation-induced proliferation of human mammary carcinoma (AG1478) cells requires activation of EGFR; it indicates that accelerated repopulation during a course of ionising radiation might be mediated through the EGFR pathway.
54. Akimoto, T. et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin. Cancer Res. 5, 2884-2890 (1999).
55. Milas, L. et al. Relationship between cyclin D1 expression and poor radioresponse of murine carcinomas. Int. J. Radiat Oncol. Biol. Phys. 52, 514-521 (2002).
56. Grandis J. R., et al. Levels of TGF-α and EGFR protein in head and neck squamous cell carinoma and patient survival. J. Natl Cancer Inst 90, 824-832 (1998).
57. Ang, K. K. et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 62, 7350-7356 (2002).
58. Eriksen, J. G., Steiniche, T., Askaa, J., Alsner, J. & Overgaard, J. The prognostic value of epidermal growth factor receptor is related to tumour differentiation and the overall treatment time of radiotherapy in squamous cell carcinomas of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 58, 561-566 (2004).
59. Norton, L. & Simon, R. Tumour size, sensitivity to therapy, and design of treatment schedules. Cancer Treat. Rep. 61 1307-1317 (1977). This paper provided an early model of tumour regrowth based on the application of the Gompertz equation. Although it did not use the term 'repopulation' the model is consistent with accelerated repopulation after cancer treatment.
60. Norton, L. & Simon, R. The Norton-Simon hypothesis revisited. Cancer Treat. Rep 70, 163-169 (1986).
61. Davis, A. J. & Tannock, J. F. Repopulation of tumour cells between cycles of chemotherapy: a neglected factor. Lancet Oncol. 1, 86-93 (2000). This paper provided models for the effect on tumour volume of repopulation between courses of chemotherapy. It showed that the common clinical experience of initial tumour response followed by regrowth during repeated courses of chemotherapy can be explained by accelerating repopulation.
62. Withers, H. R. in Radiation Research: A Twentieth Century Perspective, Vol. II Congress Proceedings (ed. Dewey, W. C.) 26-31 (Academic, New York, 1991).
63. Freyer, J. P. & Sutherland, R. M. Proliferative and donogenic heterogeneity of cells from EMT6/Ro multicellular spheroids induced by the glucose and oxygen supply. Cancer Res. 46, 3513-3520 (1986).
64. Bredel-Geissler, A., Karbach, U., Walenta, S., Vollrath, L. & Mueller-Klieser, W. Proliferation-associated oxygen consumption and morphology of tumour cells in monolayer and spheroid culture. J. Cell. Physiol. 153, 44-52 (1992).
65. Durand, R. E. Distribution and activity of antineoplastic drugs in a tumour model. J. Natl Cancer Inst. 81, 146-152 (1989).
66. Lankelma, J. et al. Doxorubicin gradients in human breast cancer. Clin. Cancer Res. 5, 1703-1707 (1703).
67. Jain, R. K. Delivery of molecular and cellular medicine to solid tumours. Adv. Drug Deliv. Rev. 46, 149-168 (2001).
68. Tannock, I. F. Tumour physiology and drug resistance. Cancer Metastasis Rev. 20, 123-132 (2001).
69. Tannock, I. F., Lee, C. M., Tunggal, J. K., Cowan, D. S. & Egorin, M. J. Limited penetration of anticancer drugs through tumour tissue: a potential cause of resistance of solid tumours to chemotherapy. Clin. Cancer Res. 8, 878-8784 (2002).
70. Huxham, L. A., Kyle, A. H., Baker, J. H., Nykilchuk, L. K. & Minchinton, A. I. Microregional effects of gemcitabine in HCT-116 xenografts. Cancer Res. 64, 6537-6541 (2004). This study showed that repopulation occurred predominantly from distal cells that had a low rate of proliferation in the untreated tumour.
71. Withers, H. R. Biologic basis for altered fractionation schemes. Cancer 55, 2086-2095 (1985). This paper discusses the radiobiological principles that underlie the choice of an accelerated fractionation radiotherapy schedule.
72. Peters, L. J., Ang, K. K. & Thames, H. D., Jr. Accelerated fractionation in the radiation treatment of head and neck cancer. A critical comparison of different strategies. Acta Oncol. 27, 185-194 (1988).
73. Norin, T. et al. Conventional and superfractionated radiation therapy in Burkitt's lymphoma. Acta Radiol. Ther. Pnys. Biol. 10, 545-557 (1971).
74. Bourhis, J. et al. Meta-analysis of conventional vs altered fractionated radiotherapy in head and neck squamous cell carcinoma (HNSCC): final analysis. Int. J. Radiat Oncol. Biol. Phys. 60, S190-S191 (2004).
75. Overgaard, J. et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomized controlled trial. Lancet 362, 933-940 (2003).
76. Skladowski, K., Law, M. G., Maciejewski, B. & Steel, G. G. Planned and unplanned gaps in radiotherapy: the importance of gap position and gap duration. Radiother. Oncol. 30, 109-120 (1994).
77. Poulsen, M. G. et al. A randomized trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study. Radiother. Oncol. 60, 113-122 (2001).
78. Dische, S. et al. A randomized multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother. Oncol. 44, 123-136 (1997).
79. Saunders, M. et al. (and on behalf of the CHART Steering Committee) Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomized multicentre trial CHART Steering Committee. Lancet 350, 161-165 (1997).
80. Saunders, M. et al. (and on behalf of the CHART Steering Committee) Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomized multicentre trial. Radiother. Oncol. 52, 137-148 (1999).
81. Citron, M. L. et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J. Clin. Oncol. 21, 1431-1439 (2003). This report of a large randomized trial of adjuvant chemotherapy for patients with breast cancer showed improved survival for those receiving dose-dense chemotherapy delivered at two-week intervals with growth factor support, compared with those receiving standard three-week scheduling.
82. Pfreundschuh, M. et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 104, 634-641 (2004).
83. Sternberg, C. N. et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumours: European Organization for Research and Treatment of Cancer Protocol no. 30924. J. Clin. Oncol. 19, 2638-2646 (2001).
84. Baldini, E. et al. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann. Oncol. 14, 227-232 (2003).
85. Browman, G. P. et al. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer: A systematic review of the published literature with subgroup analysis. Head Neck 23, 579-589 (2001).
86. Bourhis, J. & Pignon, J. P. Meta-analyses in head and neck squamous cell carcinoma. What is the role of chemotherapy? Hematol. Oncol. Clin. North Am. 13, 769-775, vii (1999).
87. Eifel, P. J. et al. Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of Radiation Therapy Oncology Group Trial (RTOG) 90-01. J Clin. Oncol. 22, 872-880 (2004).
88. Tannock, I. F. Treatment of cancer with radiation and drugs. J. Clin. Oncol. 14, 3156-3174 (1996).
89. Peters, L. J. & Withers, H. R. Applying radiobiological principles to combined modality treatment of head and neck cancer - the time factor. Int. J Radiat. Oncol. Biol. Phys. 39, 831-836 (1997).
90. Wendt, T. G. et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J. Clin. Oncol. 16, 1318-1324 (1998).
91. Keane, T. J. et al. A randomized trial of radiation therapy compared to split course radiation therapy combined with mitomycin C and 5 fluorouracil as initial treatment for advanced laryngeal and hypopharyngeal squamous carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 25, 613-618 (1993).
92. Furuse, K. et al. Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J. Clin. Oncol. 17, 2692-2699 (1999).
93. Rischin, D. et al. Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: A randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J. Clin. Oncol. 23, 79-87 (2005).
94. Corry, J. et al. Radiation with concurrent late chemotherapy intensification ('chemoboost') for locally advanced head and neck cancer. Radiother. Oncol. 54, 123-127 (2000).
95. Garden, A. S. et al. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase II trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J. Clin. Oncol. 22, 2856-2864 (2004).
96. Bonner, J. A. et al. Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J. Clin. Oncol. 22, 5507 (2004).
97. Ma, B. B., Bristow, R. G., Kim, J. & Siu, L. L. Combined-modality treatment of solid tumours using radiotherapy and molecular targeted agents. J. Clin. Oncol. 21, 2760-2776 (2003).
98. Wu, L. & Tannock, I. F. Selective estrogen receptor modulators as inhibitors of repopulation of human breast cancer cell lines after chemotherapy. Clin. Cancer Res. 9, 4614-4618 (2003).
99. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumours to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314-10319 (2001).
100. Visakorpi, T. The molecular genetics of prostate cancer. Urology 62, 3-10 (2003).
101. Wu, H. Birle, D. C. & Tannock, I. F. Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. Cancer Res. 65, 2825-2831 (2005).