Cell Proliferation and the Principles of Cancer Therapy

  • W. M. Gregory


The guiding principles on which a great deal of modern cancer therapy is based originate with experiments undertaken by Skipper and colleagues in the 1960s (Skipper et al. 1964, 1967). As a result of his investigations of experimental tumour systems, Skipper concluded that a given dose or course of (chemo)therapy will kill a constant fraction of the cell population, rather than a constant number of cells. He went on to consider the consequences of tumours having different growth rates, and concluded that chemotherapy gave a greater fractional cell-kill to more rapidly growing tumours, and was more likely to be curative in such cases (Skipper and Perry 1970). It also appeared that larger tumours generally grew more slowly, and that the lack of responsiveness of such tumours was related to this slower rate of proliferation (Shackney 1970; Steel et al. 1976).


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akanuma A (1978) Parameter analysis of gompertzian function growth model in clinical tumours. Eur J Cancer 14:681–688PubMedCrossRefGoogle Scholar
  2. Barnard NJ, Hall PA, Lemoine NJ and Kadar N (1987) Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables. J Pathol 152:287–295PubMedCrossRefGoogle Scholar
  3. Bell R, Rohatiner AZS, Slevin ML et al. (1982) Short-term treatment for acute myelogenous leukaemia. Br Med J 284:1221–1229CrossRefGoogle Scholar
  4. Birkhead BG and Gregory WM (1984) A mathematical model of the effects of drug resistance in cancer chemotherapy. Math Biosci 72:59–70CrossRefGoogle Scholar
  5. Birkhead BG, Rankin EM, Gallivan S, Dones L and Rubens RD (1987) A mathematical model of the development of drug resistance to cancer chemotherapy. Eur J Cancer Clin Oncol 23: 1421–1427PubMedCrossRefGoogle Scholar
  6. Bonadonna G, Valagussa P, Rossi A et al. (1985) Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat 5:95–115PubMedCrossRefGoogle Scholar
  7. Bonadonna G and Valagussa P (1987) Current status of adjuvant chemotherapy for breast cancer. Semin Oncol 14:8–22PubMedGoogle Scholar
  8. Bonadonna G, Valagussa P and Santoro A (1986) Alternating non-cross resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease. Ann Intern Med 104:739–746PubMedCrossRefGoogle Scholar
  9. Connors JM and Klimo P (1988) MACOP-B chemotherapy for malignant lymphomas and related conditions: 1987 update and additional observations. Semin Haematol 25:41–46Google Scholar
  10. D’Angio GJ, Evans AE, Breslow N et al. (1976) The treatment of Wilms’ tumour. Results of the National Wilms’ Tumour Study. Cancer 38:633–646PubMedCrossRefGoogle Scholar
  11. D’Angio GJ, Evans A, Breslow N et al. (1981) The treatment of Wilms’ tumour. Results of the Second National Wilms’ Tumour Study. Cancer 47:2302–2311PubMedCrossRefGoogle Scholar
  12. D’Angio GJ, Breslow N, Beckwith JB et al. (1989) Treatment of Wilms’ tumor. Results of the Third National Wilms’ Tumor Study. Cancer 64:349–360PubMedCrossRefGoogle Scholar
  13. Demicheli R (1980) Growth of testicular neoplasm lung metastases: tumour specific correlation between two Gompertzian parameters. Eur J Cancer 16:1603–1608PubMedCrossRefGoogle Scholar
  14. De Vita VT, Simon RM, Hubbard SM et al. (1980) Curability of advanced Hodgkin’s disease with chemotherapy. Long term follow-up of MOPP-treated patients at the National Cancer Institute. Ann Intern Med 92:587–594CrossRefGoogle Scholar
  15. Fisher RI, De Vita VT Jr and Hubbard SM (1983) Diffuse aggresive lymphomas: increased survival after alternating flexible sequences of ProMACE and MOPP chemotherapy. Ann Intern Med 98:304–309PubMedCrossRefGoogle Scholar
  16. Freireich EJ, Gehan E, Frei III E et al. (1963) The effect of 6-mercaptopurine on the duration of steroid-induced remissions in acute leukaemia: a model for evaluation of other potentially useful therapy. Blood 21:699–716Google Scholar
  17. Ganesan TS, Wrigley PF, Murray PA et al. (1990) Radiotherapy for stage I Hodgkin’s disease: 20 years experience at St Bartholomew’s Hospital. Br J Cancer 62:314–318PubMedCentralPubMedCrossRefGoogle Scholar
  18. Gatter KC, Dunnill MS, Gerdes J, Stein H and Mason DY (1986) New approach to assessing lung tumours in man. J Clin Pathol 39:590–593PubMedCrossRefGoogle Scholar
  19. Gerdes J, Dallenbach F, Lennert K, Lemke H and Stein H (1984) Growth fractions in malignant non-Hodgkin’s lymphoma as determined in situ by the monoclonal antibody Ki67. Haematol Oncol 2:365–371CrossRefGoogle Scholar
  20. Gerdes J, Lelle RJ, Rickartz H et al. (1986) Growth fractions in breast cancers determined in situ with monoclonal antibody Ki67. J Clin Pathol 39:977–980PubMedCrossRefGoogle Scholar
  21. Goldie JH and Coldman AJ (1979) A mathematical model for relating the drug sensitivity of tumours to their spontaneous mutation rate. Cancer Treat Rep 63:1727–1731PubMedGoogle Scholar
  22. Gore ME, Selby PJ, Viner C et al. (1989) Intensive treatment of multiple myeloma and criteria for complete remission. Lancet ii:879–882Google Scholar
  23. Greer S and Watson M (1987) Mental adjustment to cancer: its measurement and prognostic importance. Cancer Surv 6:439–453PubMedGoogle Scholar
  24. Gregory WM, Birkhead BG and Souhami RL (1988) A mathematical model of drug resistance applied to treatment for small cell lung cancer. J Clin Oncol 6:457–461PubMedGoogle Scholar
  25. Gregory WM, Reznek RH, Hallett M and Slevin ML (1990) Using mathematical models fo estimate drug resistance and treatment efficacy via CT scan measurements of tumour volume. Br J Cancer 62:671–675PubMedCentralPubMedCrossRefGoogle Scholar
  26. Gregory WM, Richards MA, Slevin ML and Souhami RL (1991) A mathematical model relating response durations to amount of sub-clinical resistant disease. Cancer Res 51:1210–1216PubMedGoogle Scholar
  27. Hall PA, Richards MA, Gregory WM, d’Ardenne AJ, Lister TA and Stansfeld AG (1988) The prognostic value of Ki67 immunostaining in Non-Hodgkin’s lymphoma. J Pathol 154:223–236PubMedCrossRefGoogle Scholar
  28. Imanaga H and Nakazato H (1977) Results of surgery for gastric cancer and effect of adjuvant mitomycin C on cancer recurrence. World J Surg 1:213–221CrossRefGoogle Scholar
  29. Klimo P and Connors JM (1985) MOPP/ABV hybrid program: combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin’s disease. J Clin Oncol 3:1174–1182PubMedGoogle Scholar
  30. Laird AK (1964) Dynamics of tumour growth. Br J Cancer 18:490–502PubMedCentralCrossRefGoogle Scholar
  31. Mackenzie AR (1966) Chemotherapy of metastatic testis cancer: results in 54 patients. Cancer 19:1369–1376PubMedCrossRefGoogle Scholar
  32. McElwain TJ and Peckham MJ (1974) Combination chemotherapy in testicular tumours. Proc R Soc Med 67:297PubMedCentralPubMedGoogle Scholar
  33. Medical Research Council’s Working Party on Lymphomas (1979) Randomised trial of two-drug and four-drug maintenance chemotherapy in advanced or recurrent Hodgkin’s disease. Br Med J 1:1105–1108CrossRefGoogle Scholar
  34. Nakajima T, Fukami A, Ohashi T and Kajitani T (1978) Long-term follow-up study of gastric cancer patients treated with surgery and adjuvant chemotherapy with mitomycin C. Int J Clin Pharmacol Biopharm 16:209–216PubMedGoogle Scholar
  35. Newlands ES, Begent RHJ, Rustin GJS, Parker D and Bagshawe KD (1983) Further advances in the management of malignant teratomas of the testis and other sites. Lancet i:948CrossRefGoogle Scholar
  36. Norton L (1988) A gompertzian model of human breast cancer growth. Cancer Res 48:7067–7071PubMedGoogle Scholar
  37. Norton L and Simon R (1977) Tumour size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 61:1307–1317PubMedGoogle Scholar
  38. Norton L and Simon R (1986) The Norton-Simon hypothesis revisited. Cancer Treat Rep 70: 163–169PubMedGoogle Scholar
  39. Oliver RTD (1986) Germ cell tumours. In: Slevin ML and Staquet MJ (eds) Randomised trials in cancer: a critical review by sites. Raven Press, New YorkGoogle Scholar
  40. Okumura Y, Ueda T, Mori T and Kitabatake T (1977) Kinetic analysis of tumour regression during the course of radiotherapy. Strahlentherapie 153:35–39PubMedGoogle Scholar
  41. Pearlman AW (1983) Doubling time and survival time. In: Stoll BA (ed) Cancer treatment: end point evaluation. John Wiley and Sons, New York, pp 279–301.Google Scholar
  42. Peckham MJ, Barrett A and Lieu KH (1983) The treatment of metastatic germ cell testicular tumours with bleomycin, etoposide and cisplatinum (BEP). Br J Cancer 47:613–619PubMedCentralPubMedCrossRefGoogle Scholar
  43. Price P, Hogan SJ and Horwich A (1990a) The growth rate of metastatic non-seminomatous germ cell testicular tumours measured by marker production doubling time - I. Theoretical basis and practical application. Eur J Cancer 26:450–453PubMedCrossRefGoogle Scholar
  44. Price P, Hogan SJ, Bliss JM and Horwich A (1990b) The growth rate of metastatic nonseminomatous germ cell testicular tumours measured by marker production doubling time - II. Prognostic significance in patients treated by chemotherapy. Eur J Cancer 26:453–457PubMedCrossRefGoogle Scholar
  45. Ramirez AJ, Craig TK, Watson JP, Fentiman IS, North WR and Rubens RD (1989) Stress and relapse of breast cancer. Br Med J 298:291–293CrossRefGoogle Scholar
  46. Rees JKH, Gray RG, Swirzky D and Hayhoe FGJ (1986) Principal results of the medical research council’s 8th acute myeloid leukaemia trial. Lancet ii: 1236–1241CrossRefGoogle Scholar
  47. Richards MA, O’Reilly SM, Howell A et al. (1990) Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy’s/Manchester trial. J Clin Oncol 8:2032–2039PubMedGoogle Scholar
  48. Rubens RD, Bartelink H and Engelsman E et al. (1989) Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy. Eur J Cancer Clin Oncol 25:667–678PubMedCrossRefGoogle Scholar
  49. Selby PJ, McElwain TJ, Nandi AC et al. (1987) Multiple myeloma treated with high dose intravenous melphalanp. Br J Haematol 66:55–62PubMedCrossRefGoogle Scholar
  50. Shackney SE (1970) A computer model for tumour growth and chemotherapy, and its application to L1210 leukemia treated with cytosine arabinoside (NSC-63878). Cancer Chemother Rep 54:399–429PubMedGoogle Scholar
  51. Shackney SE, McCormack GW and Cuchural GJ (1978) Growth patterns of solid tumours and their relation to responsiveness to therapy. Ann Intern Med 89:107–121PubMedCrossRefGoogle Scholar
  52. Skarin AT, Canellos GP and Rosenthal DS (1983) Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oncol 1:91–98PubMedGoogle Scholar
  53. Skipper HE and Perry S (1970) Kinetics of normal and leukemic leukocyte populations and re­levance to chemotherapy. Cancer Res 30:1883–1897PubMedGoogle Scholar
  54. Skipper HE, Schabel FM Jr and Wilcox WS (1964) Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 35:1–111PubMedGoogle Scholar
  55. Skipper HE, Schabel FM Jr and Wilcox WS (1967) Experimental evaluation of anticancer agents. XXI. Scheduling of arabinosylcytosine to take advantage of its S-phase specificity against leukemia cells. Cancer Chemother Rep 51:125–165PubMedGoogle Scholar
  56. Slevin ML and Staquet MJ (eds) (1986) Randomised trials in cancer: a critical review by sites. Raven Press, New YorkGoogle Scholar
  57. Slevin ML, Clark PI, Joel SP et al. (1989) A randomised trial to evaluate the effect of schedule on the activity of etoposide in small cell lung cancer. J Clin Oncol 7:1333–1340PubMedGoogle Scholar
  58. Steel GG, Adams K and Stanley J (1976) Size-dependence of the response of Lewis lung tumours to BCNU. Cancer Treatment Reports 60:1743–1748PubMedGoogle Scholar
  59. Sullivan PW and Salmon SE (1972) Kinetics of tumour growth and regression in IgG multiple myeloma. J Clin Invest 51:1967–1973CrossRefGoogle Scholar
  60. Tsukuma H, Mishima T and Oshima A (1983) Prospective study of “early” gastric cancer. Int J Cancer 31:421–426PubMedCrossRefGoogle Scholar
  61. Vaughan WP, Karp JE and Burke PJ (1984) Two-cycle timed sequential chemotherapy for adult acute nonlymphocytic leukemia. Blood 64:975–980PubMedGoogle Scholar
  62. Vugrin D, Whitmore WE Jr and Golbey RB (1983) VAB-6 combination of chemotherapy with­out maintenance in treatment of disseminated cancer of the testis. Cancer 51:211PubMedCrossRefGoogle Scholar
  63. Waxman JH, Ahmed R, Smith D et al. (1987) Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 19:159–162PubMedCrossRefGoogle Scholar
  64. Young RC, Canellos GP, Chabner BA, Schein PS and De Vita VT (1973) Maintenance chemotherapy for advanced Hodgkin’s disease in remission. Lancet i: 1339–1343CrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 1992

Authors and Affiliations

  • W. M. Gregory

There are no affiliations available

Personalised recommendations