Abstract
The presence of radiation resistant cells in solid human tumors is believed to be a major reason why radiotherapy fails to eradicate some such neoplasms. The presence of unperfused regions containing hypoxic cells may also contribute to resistance to some chemotherapeutic agents. This paper reviews the evidence that radiation resistant hypoxic cells exist in solid tumors, the assumptions and results of the methods used to detect hypoxic cells, and the causes and nature of tumor hypoxia. Evidence that radiation resistant hypoxic cells exist in the vast majority of transplanted rodent tumors and xenografted human tumors is direct and convincing, but problems with the current methodology make quantitative statements about the magnitude of the hypoxic fractions problematic. Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing. However, evidence that hypoxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive. The nature and causes of tumor hypoxia are not definitively known. In particular, it is not certain whether hypoxia is a chronic or a transient state, whether hypoxic cells are proliferating or quiescent, or whether hypoxic cells have the same repair capacity as aerobic cells. A number of new methods for assessing hypoxia are reviewed. While there are still problems with all of the new techniques, some of them have the potential of allowing the assessment of hypoxia in individual human tumors.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Crabtree HG, Cramer W: The action of radium on cancer cells. II. — Some factors determining the sensitivity of cancer cells to radium. Proc Royal Soc 113: 238–250, 1933
Mottram JC: On the alteration in the sensitivity of cells towards radiation produced by cold and anaerobiosis. Brit J Radiol 8: 32–39, 1935
Mottram JC: A factor of importance in the radiosensitivity of tumours. Brit J Radiol 9: 606–614, 1936
Thomlinson RH, Gray LH: The histological structure of some human lung cancers and the possible implications for radiotherapy. Brit J Cancer 9: 539–549, 1955
Brown JM: Evidence for acutely hypoxic cells in mouse tumors, and a possible mechanism of reoxygenation. Brit J Radiol 52: 650–656, 1979
Powers WE, Tolmach LJ: A multi-component X-ray survival curve for mouse lymphosarcoma cells irradiated in vivo. Nature 197: 710–711, 1963
Kallman RF: The phenomena of reoxygenation and its implications for fractionated radiotherapy. Radiology 105: 135–142, 1972
Moulder JE, Rockwell S: Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys 10: 695–712, 1984
Kennedy KA, Teicher BA, Rockwell S, Sartorelli C: The hypoxic tumor cell: a target for selective cancer chemotherapy. Biochem Pharm 29: 1–8, 1980
Rockwell S: Hypoxic cells as targets for cancer chemotherapy. In: Cheng YC, Goz B, Minkoff M (eds) The development of target oriented anticancer drugs. Raven Press, New York, NY, 1983, pp 157–172
Teicher BA, Lazo JS, Sartorelli AC: Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells. Cancer Res 41: 73–81, 1981
Goldacre RJ, Sylven B: A rapid method for studying tumour blood supply using systemic dyes. Nature 184: 63–64, 1959
Goldacre RJ, Sylven B: On the access of blood-borne dyes to various tumour regions. Brit J Cancer 16: 306–322, 1962
Owen LN: A rapid method for studying tumour blood supply using lissamine green. Nature 187: 795–796, 1960
Tannock I, Guttman P: Response of Chinese hamster ovary cells to anti-cancer drugs under aerobic and hypoxic conditions. Brit J Cancer 43: 245–248, 1981
Twentyman PR: Comparative chemosensitivity of exponential-versus plateau-phase cells both in vitro and in vivo. Cancer Treat Rep 60: 1719–1722, 1976
Valeriote F, VanPutten LM: Proliferation-dependent cytotoxicity of anticancer agents: A review. Cancer Res 35: 2619–2630, 1975
Bedford JS, Mitchell JB: The effect of hypoxia on the growth and radiation response of mammalian cells in culture. Brit J Radiol 47: 687–696, 1974
Brock WA, Swartzendruber DE, Grdina D: Kinetic heterogeneity in density-separated murine fibrosarcoma subpopulations. Cancer Res 42: 4999–5003, 1982
Koch CJ, Kruuv J, Frey NE, Sayder RA: Plateau phase in growth induced by hypoxia. Int J Radiat Biol 23: 67–74, 1973
Duncan W: Exploitation of the oxygen enhancement ratio in clinical practice. Brit Med Bull 29: 33–38, 1973
Fowler JF: La Ronde — radiation sciences and medical radiology. Radiother Oncol 1: 1–22, 1983
Suit HD: Modification of radiation response. Int J Radiat Oncol Biol Phys 10: 101–108, 1984
Elkind MM: Reoxygenation and its potential role in radiotherapy. In: Bond VP, Suit HD, Marcial V (eds) Conference in Time and Dose Relationships in Radiobiology as Applied to Radiotherapy. Brookhaven National Laboratory, Upton, 1970, pp 242–247
Holsti LR, Salmo M, Elkind MM: Unconventional fractionation in clinical radiotherapy. Brit J Cancer 37(Suppl III): 307–310, 1978
Littbrand B, Edsmyr F: Preliminary results of bladder carcinoma irradiated with low individual doses and a high total dose. Int J Radiat Oncol Biol Phys 1: 1059–1062, 1976
Churchill-Davidson I, Sanger C, Thomlinson RH: Oxygenation in radiotherapy. II. Clinical applications. Brit J Radiol 30: 406–422, 1957
Dische S: Hyperbaric oxygen: the Medical Research Council trials and their clinical significance. Brit J Radiol 51: 888–894, 1979
Suit H, Schlachter L, Andrews JR: ‘Oxygen effect’ and tumor size as related to response of C3H/Ba adenocarcinoma to local X-irradiation. J Nat Cancer Inst 24: 1271–1281, 1960
Dusault LA: The effect of carbogen on the response of spontaneous tumors in mice to radiotherapy. Brit J Radiol 36: 749–754, 1963
Evans NTS, Naylor PFD: The effect of oxygen breathing and radiotherapy upon the tissue oxygen tension of some human tumours. Brit J Radiol 36: 418–425, 1963
Inch WR, McCredie JA, Sutherland RM: Effect of duration of breathing 95% oxygen plus 5% carbon dioxide before X-irradiation on the cure of C3H mammary tumor. Cancer 25: 926–931, 1970
Rubin P, Hanley J, Keys HM, Marcial V, Brady L: Carbogen breathing during radiation therapy. Int J Radiat Oncol Biol Phys 5: 1963–1970, 1979
Rockwell S: Use of a perfluorochemical emulsion to improve oxygenation in a solid tumor. Int J Radiat Oncol Biol Phys 11: 97–103, 1985
Rose C, Lustig R, McIntosh N, Teicher B: A clinical trial of Fluosol DA 20% in advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 12: 1325–1328, 1986
Teicher BA, Rose CM: Perfluorochemical emulsions can increase tumor radiosensitivity. Science 223: 934–936, 1984
Balmukhanov SB, Rismohamedova R, Mussapirova N, Abdrahmonov J, Toktamisova Z, Aitkoolova S, Revesz L: Prognostic factors of radiation therapy with metronidazole of cervix cancer. Radiosens News 5: 1–2, 1986
Bush RS, Jenkin RDT, Allt WEC, Beale FA, Bean H, Dembo AJ, Pringle FR: Definitive evidence for hypoxic cells influencing cure in cancer therapy. Brit J Cancer 37(Suppl III): 302–306, 1978
Overgaard J, Hansen HS, Jorgensen R, Hansen MH: Primary radiotherapy of larynx and pharynx carcinoma — An analysis of some factors influencing local control and survival. Int J Radiat Oncol Biol Phys 12: 515–521, 1986
Baker DJ, Lindop PJ, Morgan WG, Skeggs DBL, Whittle RJM, Williams IG: Monitored regional hypoxia in radiotherapy. Brit J Radiol 39: 908–914, 1966
Suit HD: Radiation therapy given under conditions of local hypoxia for bone and soft tissue sarcoma. In: Tumors of bone and soft tissue. Year Book Medical Publishers. Chicago, 1965, pp 143–163
Begg AC, Sheldon PW, Foster JL: Demonstration of radiosensitization of hypoxic cells in solid tumours by metronidazole. Brit J Radiol 47: 399–404, 1974
Denekamp J, Hirst DG, Stewart FA, Terry NJ: Is tumor radiosensitization by misonidazole a general phenomena? Brit J Radiol 41: 1–9, 1980
Overgaard J, Hansen HS, Andersen AP, Hjelm-Hansen M, Jorgensen K, Sandberg E, Rygard J, Jensen RH, Petersen M: Misonidazole as an adjuvant to radiotherapy in the treatment of invasive carcinoma of the larynx and pharynx. In: Karcher KH, Kogelnik HD, Reinartz G (eds) Progress in Radio Oncology III, Raven Press, New York, in press, 1987
Rauth AM, Kaufman K: In vivo testing of hypoxic radiosensitizers using the KHT murine tumour assayed by the lung-colony technique. Brit J Radiol 48: 209–220, 1975
Urtasun R, Band P, Chapman JD, Feldstein ML, Mielke B, Fryer C: Radiation and high dose metronidazole in supratentorial glioblastomas. New England J Med 294: 1364–1367, 1976
Barendsen GW, Broerse JJ: Experimental radiotherapy of a rat rhabdomyosarcoma with 15 MeV neutrons and 300 kV X-rays. I. Effects of single exposures. Europ J Cancer 5: 373–391, 1969
Withers HR: Biological basis for high-LET radiotherapy. Radiology 108: 131–137, 1973
Dewhirst MW, Ozimek EJ, Gross J, Cetas TC: Will hyperthermia conquer the elusive hypoxic cell? Radiology 137: 811–817, 1980
Overgaard J: Effect of hyperthermia on the hypoxic fraction of an experimental mammary carcinoma in vivo. Brit J Radiol 54: 245–249, 1981
Moore JV, Hasleton PS, Buckley CH: Tumour cords in 52 human bronchial and cervical squamous cell carcinomas: Inferences for their cellular kinetics and radiobiology. Brit J Cancer 51: 407–413, 1985
Cater DB, Silver IA: Quantitative measurements of oxygen tension in normal tissues and in the tumours of patients before and after radiotherapy. Acta Radiol 53: 233–256, 1960
Gatenby RA, Coia LR, Richter MP, Holdofsky PJ, Engstrom P, Brown DQ, Brookland R, Broder GJ: Oxygen tension in human tumors: in vivo mapping using CT-guided probes. Radiology 156: 211–214, 1985
Mueller-Klieser W, Vaupel P, Manz R, Grunewald WA: Intracapillary oxyhemoglobin saturation in malignant tumors in humans. Int J Radiat Oncol Biol Phys 7: 1397–1404, 1981
Urtasun RC, Chapman JD, Raleigh JA, Franko AJ, Koch CJ: Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. Int J Radiat Oncol Biol Phys 12: 1263–1267, 1986
Dische S: Chemical sensitizers for hypoxic cells. Radiother Oncol 3: 97–115, 1985
Rockwell S, Moulder JE, Martin DF: Effectiveness and biological effects of techniques used to induce hypoxia in solid tumors. Radiother Oncol 5: 311–319, 1986
Brownlee KA: Simple linear regression. In: Statistical Theory and Methodology in Science and Engineering, 2nd edition. John Wiley & Sons Inc, New York, 1965, pp 605–611
Finney DJ: Statistical Methods in Biological Assay. Hafner Publishing Co., New York, 1964
Rockwell S: Maintenance of tumor systems and appropriate treatment techniques. In: Kallman RF (ed) Rodent Tumor Models in Experimental Cancer Therapy. Pergamon Press, New York, in press, 1987
Denekamp J, Terry NHA, Sheldon PW, Chu AM: The effect of pentobarbital anaesthesia on the radiosensitivity of four mouse tumors. Int J Radiat Biol 35: 277–280, 1979
Moulder JE, Martin DF: Hypoxic fraction determinations with the BA1112 rat sarcoma: Variation within and among assay techniques. Radiat Res 98: 536–548, 1984
Sheldon PW, Chu AM: The effect of anesthetics on the radiosensitivity of a murine tumor. Radiat Res 79: 568–578, 1979
Sheldon PW, Hill SA, Moulder JE: Radioprotection by pentobarbitone sodium of a murine tumor in vivo. Int J Radiat Biol 32: 571–575, 1977
Wallen CA, Michaelson SM, Wheeler KT: Evidence for unconventional radiosensitivity of rat 9L subcutaneous tumors. Radiat Res 84: 529–541, 1980
Cater DB, Hill DW, Lindop PJ, Nunn JF, Silver IA: Oxygen washout studies in the anesthetized dog. J Appl Physiol 18: 888–894, 1963
Hill RP, Bush RS: A new method of determining the fraction of hypoxic cells in a transplantable murine sarcoma. Radiat Res 70: 141–153, 1977
Clifton KH, Briggs RC, Stone HB: Quantitative radiosensitivity studies of solid carcinomas in vivo: Methodology and effect of anoxia. J Nat Cancer Inst 36: 965–974, 1966
Denekamp J, Hill SA, Hobson B. Vascular occlusion and tumor cell death. Int J Radiat Oncol Biol Phys 19: 271–275, 1983
Powers WE, Tolmach LJ: Demonstration of an anoxic component in a mouse tumor-cell population by an in vivo assay of survival following irradiation. Radiology 83: 328–336, 1964
Tannock IF: Oxygen diffusion and the distribution of cellular radiosensitivity in tumors. Brit J Radiol 45: 515–524, 1972
Rockwell S, Moulder JE, Martin DF: Tumor-to-tumor variability in the hypoxic fractions of experimental rodent tumors. Radiother Oncol 2: 57–64, 1984
Reinhold HS: In vivo observations of tumor blood flow. In: Peterson HI (ed) Tumor Blood Circulation: Angiogenesis, Vascular Morphology, and Blood Flow of Experimental and Human Tumors. CRC Press, Boca Raton, 1979, pp 115–128
Reinhold HS, Blachiewicz B, Berg-Blok A: Reoxygenation of tumours in ‘sandwich’ chambers. Europ J Cancer 15: 481–489, 1979
Reinhold HS, Blachiewicz B, Blok A: Oxygenation and reoxygenation in ‘sandwich’ tumors. Biblio Anat 15: 270–272, 1976
Sutherland RM, Franko AJ: On the nature of the radiobiologically hypoxic fraction in tumors. Int J Radiat Oncol Biol Phys 6: 117–120, 1980
Suit H, Urano M: Repair of sublethal radiation injury in hypoxic cells of a C3H mouse mammary carcinoma. Radiat Res 37: 423–434, 1969
Hill RP, Geisbrecht J: Hypoxia and reoxygenation in the KHT sarcoma. Radiat Res 87: 419–420, 1981
Wilson JF, Fish BL, Moulder JE, Stott M: Tumor control and normal tissue tolerance in fractionated low dose rate radiotherapy. Int J Radiat Oncol Biol Phys 12(Suppl I): 162–163, 1986
Elkind MM, Whitmore GF: The radiobiology of cultured mammalian cells. Gordon & Breach, New York, 1967
Gillespie CJ, Chapman JD, Reuvers AP, Dugle DL: The inactivation of Chinese hamster cells by X-rays: Synchronized and exponential cell populations. Radiat Res 64: 353–364, 1975
Sinclair WK: The shape of radiation survival curves of mammalian cells cultured in vitro. In: Biophysical Aspects of Radiation Quality. Technical Report Series No. 58. Internat Atomic Energy Agency, Vienna, 1966, pp 21–43
Spiro IJ, Rice GC, Durand RE, Stickler R, Ling CC: Cell killing, radiosensitization and cell cycle redistribution induced by chronic hypoxia. Int J Radiat Oncol Biol Phys 10: 1275–1280, 1984
Tokita N, Carpenter SG, Raju MR: Cell-cycle distributions and radiation responses of Chinese hamster cells cultured continuously under hypoxic conditions. Brit J Radiol 57: 1137–1143, 1984
Hall EJ: The effect of hypoxia on the repair of sublethal radiation damage in cultured mammalian cells. Radiat Res 49: 405–415, 1972
Koch CJ, Meneses JJ, Harris JW: The effect of extreme hypoxia and glucose on the repair of potentially lethal and sublethal radiation damage in mammalian cells. Radiat Res 70: 542–551, 1977
Grdina DJ, Basic I, Guzzino S, Mason KA: Radiation response of cell populations irradiated in situ and separated from a fibrosarcoma. Radiat Res 66: 634–643, 1976
Shipley WU, Stanley JA, Courtenay VD, Field SB: Repair of radiation damage in Lewis Lung carcinoma cells following in situ treatment with fast neutrons and gamma rays. Cancer Res 53: 932–938, 1975
Pallavicini MG: Characterization of cell suspensions from solid tumors. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon Press, New York, 1987, in press
Porter EH: The statistics of dose/cure relationships for irradiated tumors. Part I. Brit J Radiol 53: 210–227, 1980
Fischer JJ, Moulder JE: The steepness of the dose-response curve in radiation therapy. Radiology 117: 179–184, 1975
Moore JV: Significance of the slope of curves of tumor control versus radiation dose. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon Press, New York, 1987, in press
Martin D, Moulder JE, Fischer JJ: Tumor response endpoints in the BA1112 rat sarcoma. Brit J Cancer 41(Suppl IV): 271–274, 1980
Thames HD: Direct analysis of tumor control data. In: Kallman RF (ed) Rodent Tumor Models in Experimental Cancer Therapy. Pergamon Press, New York, 1987, in press
Trott KR, Maciejewski B, Preuss-Bayer G, Skolyszewski J: Dose-response curve and split-dose recovery in human skin cancer. Radiother Oncol 2: 123–129, 1984
McNally HJ, deRonde J: Radiobiological studies of tumours in situ compared with cell survival. Brit J Cancer 41(Suppl IV): 259–265, 1980
Sheldon PW, Fowler JF: The effect of recovery from potentially lethal damage on the determination of repair and repopulation in a murine tumour. Brit J Radiol 58: 151–160, 1985
Spiro IJ, Kennedy KA, Stichler R, Ling CC: Cellular and molecular repair of x-ray induced damage: Dependence on oxygen tension and nutritional status. Radiat Res 101: 144–155, 1985
Born R, Hug O, Trott KR: The effect of prolonged hypoxia on growth and viability of Chinese hamster cells. Int J Radiat Oncol Biol Phys 1: 687–697, 1976
Rotin D, Robinson B, Tannock IF: Influence of hypoxia and an acidic environment on the metabolism and viability of cultured cells: Potential implications for cell death in tumors. Cancer Res 46: 2821–2826, 1986
Shrieve DC, Deen DF, Harris JW: Effects of extreme hypoxia on the growth and viability of EMT6/SF mouse tumor cells in vivo. Cancer Res 43: 3521–3527, 1983
McNally NJ: A comparison of the effect of radiation on tumour growth delay and cell survival. The effect of oxygen. Brit J Radiol 46: 450–455, 1973
Begg AC: Principles and practices of the tumor growth delay assay. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon Press, New York, 1987, in press
Begg AC, Terry NHA: Stromal radiosensitivity: influence of tumour type on the tumor bed effect assay. Brit J Radiol 58: 93–96, 1985
Hewitt HB, Blake ER: The growth of transplanted murine tumors in pre-irradiated sites. Brit J Cancer 22: 808–824, 1968
Ito H, Barkley T: Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed. Int J Radiat Oncol Biol Phys 11: 547–553, 1985
Trott KR, Kummermehr J: Split dose recovery of a mouse tumor and its stroma during fractionated irradiation. Brit J Radiol 55: 841–846, 1982
Curtis SB, Tenforde TS: Assessment of tumour response in a rat rhabdomyosarcoma. Brit J Cancer 41(Suppl IV): 266–270, 1980
Thomlinson RH, Craddock EA: The gross response of an experimental tumour to single doses of X-rays. Brit J Cancer 21: 108–123, 1967
Gonzalez-Gonzales D, Haveman J: Effects of irradiation by single or multiple fractions per day on a transplantable murine mammary carcinoma. Brit J Radiol 55: 916–921. 1982
McNally NJ: A low oxygen-enhancement ratio for tumour-cell survival as compared with that for tumour-growth delay. Int J Radiat Biol 22: 407–410, 1972
Hawkes MJ, Hill RP, Lindop PJ, Ellis RE, Rotblat J: The response of C3H mammary tumours to irradiation in single and fractionated doses. Brit J Radiol 41: 134–141. 1968
Wheeler KT, Wallen CA: Is cell survival a determinant of the in situ response of 9L tumors. Brit J Cancer 41(Suppl IV): 299–303, 1980
Leith JT, Schilling WA, Wheeler KT: Cellular radiosensitivity of a rat brain tumor. Cancer 35: 1545–1550, 1975
Urano M, Kahn J: The change in hypoxic and chronically hypoxic cell fraction in murine tumors treated with hyperthermia. Radiat Res 96: 549–559, 1984
McNally NJ, Sheldon PW: The effect of radiation on tumour growth delay, cell survival and cure of animals using a single tumour system. Brit J Radiol 50: 321–328, 1977
McNally HJ: A comparison of the effects of radiation on tumour growth delay and cell survival. The effect of radiation quality. Brit J Radiol 48: 141–145, 1975
Rasey JS, Carpenter RE, Nelson NJ: Response of EMT-6 tumors to single fractions of X-rays and cyclotron neutrons: Evaluation and comparison of multiple endpoints. Radiat Res 71: 430–446, 1977
Stephens TC, Peacock JH: Comparison of growth delay and cell survival as end-points of tumour response following treatment with combinations of cytotoxic agents. Brit J Cancer 41(Suppl IV): 288–293, 1980
Twentyman PR: Experimental chemotherapy studies: intracomparison of assays. Brit J Cancer 41(Suppl IV): 279–287, 1980
McNally NJ, George KC, deRonde J: Recovery from sublethal damage by acutely hypoxic tumor cells in vivo and in vitro. Brit J Radiol 52: 642–649, 1979
Reinhold HS: Quantitative evaluation of the radiosensitivity of cells of a transplantable rhabdomyosarcoma in the rat. Europ J Cancer 2: 33–42, 1966
Hill RP, Bush RS, Young P: The effect of anaemia on the fraction of hypoxic cells in an experimental tumour. Brit J Radiol 44: 299–304, 1971
VanPutten LM, Kallman RF: Oxygenation status of a transplantable tumor during fractionated radiation therapy. J Nat Cancer Inst 40: 441–451, 1968
Stephens TC, Peacock JH, Sheldon PW: Influence of in vitro assay conditions on the assessment of radiobiological parameters of the MT tumour. Brit J Radiol 53: 1182–1187, 1980
Moulder JE, Rockwell S: Comparison of tumor assay methods. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon Press, New York, 1987, in press
Fowler JF, Sheldon PW, Begg AC, Hill SA, Smith AM: Biological properties and response to X-rays of first generation transplants of spontaneous mammary carcinomas in C3H mice. Int J Radiat Biol 27: 463–480, 1975
Peters LJ: Modification of the radiocurability of a syngeneic murine squamous carcinoma by its site of growth, by electron-affinic drugs, and by ICRF 159. Brit J Radiol 49: 708–715, 1976
Guichard M, Courdi A, Fertil B, Malaise EP: Radiosensitivity of lymph node metastases versus initial subcutaneous tumors in nude mice. Radiat Res 78: 278–285, 1979
Dorie MJ, Kallman RF: Reoxygenation in the RIF-1 tumor. Int J Radiat Oncol Biol Phys 10: 687–693, 1984
Dorie MJ, Kallman RF: Reoxygenation of the RIF-1 tumor after fractionated radiotherapy. Int J Radiat Oncol Biol Phys 12: 1853–1859, 1986
Rockwell S, Loomis R: Effects of sodium pentobarbital on the radiation response of EMT6 cells in vitro. Radiat Res 81: 292–302, 1980
Pallavicini MG, Hill RP: Effect of tumor blood flow manipulations on radiation response. Int J Radiat Oncol Biol Phys 9: 1321–1325, 1983
Thorndyke C, Meeker BE, Thomas G, Lakey WH, McPhee MS, Chapman JD: The radiation sensitivities of R3327-H and R3327-AT rat prostate adenocarcinomas. J Urol 134: 191–198, 1985
Hewitt HB: The choice of animal tumors for experimental studies of cancer therapy. Advances in Cancer Research 27: 149–200, 1978
Hewitt HB, Blake ER, Walder AS: A critique of the evidence for active host defense against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Brit J Cancer 33: 241–259, 1976
Siemann DW: Satisfactory and unsatisfactory tumor models: Factors influencing the selection of a tumor model for experimental evaluation. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon Press, New York, 1987, in press
Kallman RF: Oxygenation and reoxygenation of a mouse carcinoma. In: Duplan JF, Chapiro A (eds) Advances in radiation research (biology and medicine). Gordon and Breach, New York, 1973, pp 1195–1204
Rockwell S, Kallman RF: Cellular radiosensitivity and tumor radiation response in the EMT6 tumor cell system. Radiat Res 53: 281–294, 1973
Field SB, Jones T, Thomlinson RH: The relative effects of fast neutrons and X-rays on tumours and normal tissue in the rat. Part II. Fractionation: recovery and reoxygenation. Brit J Radiol 41: 597–607, 1968
Hermens AF, Barendsen GW: Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after irradiation. Europ J Cancer 5: 173–189, 1969
Tenforde TS, Afzal SMJ, Parr SS, Howard J, Lyman JT, Curtis SB: Cell survival in rat rhabdomyosarcoma tumors irradiated in vivo with extended-peak silicon ions. Radiat Res 92: 208–216, 1982
Tenforde TS, Curtis SB, Crabtree KE, Tenforde SD, Schilling WA, Howard J, Lyman JT: In vivo cell survival and volume response characteristics of rat rhabdomyosarcoma tumors irradiated in the extended peak region of Carbon- and Neon-ion beams. Radiat Res 83: 42–56, 1980
Rockwell S: In vivo-in vitro tumor cell lines: Characteristics and limitations as models for human cancer. Brit J Cancer 41(Suppl IV): 118–122, 1980
Steel GG: Growth Kinetics of Tumours. Clarenden Press, Oxford, 1977
Chavaudra N, Guichard M, Malaise EP: Hypoxic fractions and repair of potentially lethal radiation damage in two human melanomas transplanted into nude mice. Radiat Res 88: 56–68, 1981
Flaten TP, Rofstad BK, Brustad T: Radiation response of two human malignant melanomas grown in athymic nude mice. Europ J Cancer 17: 527–532, 1981
Guichard M, Dertinger H, Malaise EP: Radiosensitivity of four human tumor xenografts. Influence of hypoxia and cell-cell contact. Radiat Res 95: 602–609, 1983
Guichard M, Gosse C, Malaise EP: Survival curve of a human melanoma in nude mice. J Nat Cancer Inst 58: 1665–1669, 1977
Rofstad EK: Radiation response of the cells of a human malignant melanoma xenograft: Effect of hypoxic cell radiosensitizers. Radiat Res 87: 670–683, 1981
Courtenay VD, Smith IE, Peckham MJ, Steel GG: In vitro and in vivo radiosensitivity of human tumour cells obtained from a pancreatic carcinoma xenograft. Nature 263: 771–772, 1976
Gray LH: Radiobiological basis of oxygen as a modifying factor in radiation therapy. Amer J Roent 85: 803–815, 1961
Hewitt HB, Blake ER: Effect of induced host anaemia on the viability and radiosensitivity of murine malignant cells in vivo. Brit J Cancer 25: 323–336, 1971
Rofstad EK: Human tumor xenografts in radiotherapeutic research. Radiother Oncol 3: 35–46, 1985
Steel GG, Peckham MJ: Human tumour xenografts: a critical appraisal. Brit J Cancer 41(Suppl IV): 133–141, 1980
Tanooka H, Tokuzen R, Tanaka K: Radiation response of autochthonous mammary tumors in SHN mice. Gann 72: 578–582, 1981
Tanooka H, Hoshino H, Tanaka K, Nagase M: Experimental radiation therapy and apparent radioresistance of autochthonous tumors subcutaneously induced with 3-methylcolanthrene in mice. Cancer Res 40: 2547–2551, 1980
Kallman RF, Tapley ND: Radiation sensitivity and recovery patterns of spontaneous and isologously transplanted mouse tumors. Acta Int Contre Cancer 20: 1216–1218, 1964
Suit HD, Shalek RJ: Response of anoxic C3H mouse mammary carcinoma isotransplants (1–25 cu mm) to X irradiation. J Nat Cancer Inst 31: 479–495, 1963
Tannock I, Howes A: The response of viable tumor cords to a single dose of radiation. Radiat Res 55: 477–486, 1973
Koch CJ, Kruuv J, Frey HE: The effect of hypoxia on the generation time of mammalian cells. Radiat Res 53: 43–48, 1973
Shrieve DC, Begg AC: Cell cycle kinetics of aerated, hypoxic, and re-aerated cells in vitro using flow cytometric determination of cellular DNA and incorporated bromodeoxyuridine. Cell Tissue Kinet 18: 641–652, 1985
Loffler M: Towards a further understanding of the growth-inhibiting action of oxygen deficiency. Exp Cell Res 157: 195–206, 1985
Loffler M, Schimpff-Weiland G, Follman H: Deoxycytidylate shortage is a cause of G1 arrest of ascites tumor cells under oxygen deficiency. FEBS Letters 156: 72–76, 1983
Petterson EO, Lindmo T: Inhibition of cell cycle progression by acute treatment with various degrees of hypoxia: modifications induced by low concentrations of misonidazole present during hypoxia. Brit J Cancer 48: 809–817, 1983
Tubiana M: The kinetics of tumour cell proliferation and radiotherapy. Brit J Radiol 44: 325–347, 1971
Tannock IF: The relationship between cell proliferation and the vascular system in a transplanted mouse tumor. Brit J Cancer 22: 258–273, 1968
Tannock IF: Population kinetics of carcinoma cells, capillary endothelial cells, and fibroblasts in a transplanted mouse mammary tumor. Cancer Res 30: 2470–2476, 1970
Rockwell SC, Kallman RF, Fajardo LF: Characteristics of a serially transplanted mouse mammary tumor and its tissue culture adapted derivative. J Nat Cancer Inst 49: 735–749, 1972
Kallman RF, Combs CA, Franko AJ, Furlong BM, Kelley SD, Kemper HL, Miller RG, Rapacchietta D, Schoenfeld D, Takahashi M: Evidence for the recruitment of noncycling clonogenic tumor cells. In: Meyn RE, Withers HR (eds) Radiation Biology in Cancer Research. Raven Press, New York, 1980, p 397–414.
Hermens AF, Barendsen GW: The proliferative status and clonogenic capacity of tumour cells in a transplantable rhabdomyosarcoma of the rat before and after irradiation with 800 rad of X-rays. Cell Tissue Kinet 11: 83–100, 1978
Bateman AE, Steel GG: The proliferative state of clonogenic cells in the Lewis Lung tumor after treatment with cytotoxic drugs. Cell Tissue Kinet 11: 445–454, 1978
Rockwell S, Frindel E, Valleron AJ, Tubiana M: Cell proliferation in EMT6 tumors treated with single dose of X-rays or hydroxyurea. I. Experimental results. Cell Tissue Kinet 11: 279–289, 1978
Pallavicini MG, Lalande ME, Miller RG, Hill RP: Cell cycle distribution of chronically hypoxic cells and determination of the clonogenic potential of cells accumulated in G2+M phases after irradiation of a solid tumor in vivo. Cancer Res 39: 1891–1897, 1979
Allison D, Anderson S, Ridolpho P, Meyne J: Variation in DNA metabolism of MCa-II tumor cells grown in vivo and in vitro. Cell Tissue Kinet, in press, 1986
Denekamp J, Stewart FA: Evidence for repair capacity in mouse tumors relative to skin. Int J Radiat Oncol Biol Phys 5: 2003–2010, 1979
Petterson EO, Christensen T, Bakke O, Oftebro R: A change in the oxygen effect throughout the cell-cycle of human cells of the line NH1K 3025 cultured in vitro. Int J Radiat Biol 31: 171–184, 1977
Gray LH, Conger AD, Ebert M, Hornsey S, Scott OCA: The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Brit J Radiol 26: 638–648, 1953
Howard-Flanders P, Alper T: The sensitivity of micro-organisms to irradiation under controlled gas conditions. Radiat Res 7: 518–540, 1957
Kallman RF, Rockwell S: Effects of radiation on animal tumor models. In: Becker FF (ed) Cancer: A Comprehensive Treatise. Plenum Publishing Co., New York, 1977, pp 225–279
Shrieve DC, Harris JW: The in vitro sensitivity of chronically hypoxic EMT6/SF cells to x-radiation and hypoxic cell radiosensitizers. Int J Radiat Biol 48: 127–138, 1985
Littbrand B, Revesz L: The effect of oxygen on cellular survival and recovery after irradiation. Brit J Radiol 42: 914–924, 1969
Foster CJ, Malone J, Orr JS, MacFarlane DE: The recovery of the survival curve shoulder after protracted hypoxia. Brit J Radiol 44: 540–555, 1971
Djordjevic B, Dymbort G: Potentiation of radiation effects in hypoxic HeLa cells. Radiology 125: 525–527, 1977
Howes AE: An estimation of changes in proportions and absolute numbers of hypoxic cells after irradiation of transplanted C3H mouse mammary tumours. Brit J Radiol 42: 441–447, 1969
Howes AE, Page A, Fowler JF: The effect of single and fractionated doses of X-rays in the effective proportion of hypoxic cells in C3H mouse mammary tumors. Brit J Radiol 45: 250–256, 1972
Thomlinson RH: Reoxygenation as a function of tumor size and histopathological type. In: Bond VP, Suit HD, Marcial V (ed) Conference in Time and Dose Relationships in Radiation Biology as Applied to Radiotherapy. Brookhaven National Laboratory, Upton 1970, pp 242–247
Thomlinson RH: The oxygen effect and radiotherapy with fast neutrons. Europ J Cancer 7: 139–144, 1971
Little JB, Hahn GM, Frindel E, Tubiana M: Repair of potentially lethal radiation damage in vitro and in vivo. Radiology 106: 689–694, 1973
Urano M, Nesumi N, Ando K, Koike S, Ohnuma N: Repair of potentially lethal radiation damage in acutely and chronically hypoxic tumor cells. Radiology 118: 447–457, 1976
Suit HD, Howes AE, Hunter N: Dependence of response of a C3H mammary carcinoma to fractionated irradiation on fraction number and intertreatment interval. Radiat Res 72: 440–454, 1977
Chapman JD: The detection and measurement of hypoxic cells in solid tumors. Cancer 54: 2441–2449, 1984
Chapman JD, Franko AJ, Koch CJ: The fraction of hypoxic clonogenic cells in tumor populations. In: Fletcher GH, Nervi C, Withers HR (eds) Biological Bases and Clinical Implications of Tumor Radioresistance. Masson, New York, 1983, pp 61–73
Franko AJ: Misonidazole and other hypoxia markers: Metabolism and applications. Int J Radiat Oncol Biol Phys 12: 1195–1202, 1986
Chapman JD, Franko AJ, Sharplin J: A marker for hypoxic cells in tumors with potential clinical applicability. Brit J Cancer 43: 546–550, 1981
Franko AJ, Koch CJ: Binding of misonidazole to V79 spheroids and fragments of Dunning rat prostatic and human colon carcinomas in vitro: diffusion of oxygen tumor and reactive metabolites. Int J Radiat Oncol Biol Phys 10: 1333–1336, 1984
Hirst DG, Hazelhurst JL, Brown JM: Changes in misonidazole binding with hypoxic fraction. Int J Radiat Oncol Biol Phys 11: 1349–1355, 1985
Garrecht BM, Chapman JD: The labeling of EMT-6 tumours in BALB/C mice with 14C misonidazole. Brit J Radiol 56: 745–753, 1983
Rasey JS, Krohn K, Freauff S, Larson SM: Brominated misonidazole as a probe for hypoxic cells and as a radiosensitizer. Radiat Res 87: 455, 1981
Rasey JS, Krohn KA, Freauff S: Bromomisonidazole: Synthesis and characterization of a new radiosensitizer. Radiat Res 91: 542–554, 1982
Olive PL, Durand RE: Fluorescent nitroheterocycles for identifying hypoxic cells. Cancer Res 43: 3276–3280 1983
Begg AC, Engelhardt EL, McNally NJ, Terry NHA, Wardman P: Nitroakridin 2582: A fluorescent nitroacridine stain for identifying hypoxic cells. Brit J Radiol 56: 970–973, 1983
Olive PL, Chaplin DC: Oxygen and nitroreductase-dependent binding of AF-2 in spheroids and murine tumors. Int J Radiat Oncol Biol Phys 12: 1247–1250, 1986
Olive PL, Rasey JS, Durand RE: Comparison between the binding of [3H]misonidazole and AF-2 in Chinese hamster V79 spheroids. Radiat Res 105: 105–114, 1986
Gonsalvez M, Thurman RG, Chance B, Reinhold H: Regional variation in the oxygenation of mouse mammary tumours in vivo demonstrated by fluorescence of pyridine nucleotide. Brit J Radiol 45: 510–514, 1972
Keyes SR, Fracasso PM, Heimbrook DC, Rockwell S, Sligar SG, Sartorelli AC: Role of NADPH-cytochrome c reductase and DT-diaphorase in the biotransformation of mitomycin-C. Cancer Res 44: 5638–5643, 1984
Rasey JS, Hoffman JM, Spence AM, Krohn KA: Hypoxia mediated binding of misonidazole to non-malignant tissue. Int J Radiat Oncol Biol Phys 12: 1255–1258, 1986
Sutherland RM, Keng P, Conroy PJ, McDermott D, Bareham BJ, Passalacqua W: In vitro hypoxic cytotoxicity of nitroimidazoles: Uptake and cell cycle phase selectivity. Int J Radiat Oncol Biol Phys 8: 745–748, 1982
Puffer HW, Warner NE, Schaeffer LD, Wetts RW, Bradbury M: Preliminary observations of oxygen levels in microcirculation of tumors in C3H mice. In: Orte J (ed) International symposium on oxygen transport to tissue. Plenum Press, New York, 1976, pp 605–610
Vaupel P: Hypoxia in neoplastic tissue. Microvasc Res 13: 399–408, 1977
Vaupel PW, Otte J, Manz R: Oxygenation of malignant tumors after localized microwave hyperthermia. Radiat Env Biophys 20: 289–300, 1982
Jirtle R, Clifton KH, Rankin JHG: Measurement of mammary blood flow in unanesthetized rats. J Nat Cancer Inst 60: 881–886, 1978
Allalunis-Turner J, Chapman JD: The in vitro sensitivities to radiation and misonidazole of mouse bone marrow cells derived from different microenvironments. Int J Radiat Biol 49: 415–422, 1986
Evanochko WT, Ng TC, Glickson JD, Durant JR, Corbett TH: Human tumors as examined by in vitro 31P NMR in athymic mice. Biochem Res Commun 109: 1346–1352, 1982
Evelhoch JL, Sapareto SA, Nussbaum GH, Ackerman JJH: Correlations between 31P NMR spectroscopy and 15O perfusion measurements in the RIF-1 murine tumor in vivo. Radiat Res 106: 122–131, 1986
Maris JM, Evans AE, McLaughlin AC, D'Angio GJ, Bollinger L, Manos H, Chance B: 31P nuclear magnetic resonance spectroscopic investigations of human neuroblastoma in situ. New Eng J Med 23: 1500–1505, 1985
Ng TC, Evanochko WT, Hiramoto RN, Ghanta VK, Lilly MB, Lawson AJ, Corbett TH, Durant JR, Glickson JD: 31P NMR spectroscopy of in vivo tumors. J Magnet Res 49: 271–286, 1982
Raleigh JA, Franko AJ, Treiber EO, Lunt JA, Allen PS: Covalent binding of a fluorinated 2-nitroimidazole to EMT6 tumors in Balb/C mice: Detection by F-19 nuclear magnetic resonance at 2.35 T. Int J Radiat Oncol Biol Phys 12: 1243–1246, 1986
Lai CS, Hopwood LE, Hyde JS, Lukiewicz SJ: ESR studies of O2 uptake by Chinese hamster ovary cells during the cell cycle. Proc Nat Acad Sci 79: 1166–1170, 1982
Halpern HJ, Spencer DP, vanPolen J, Bowman MK, Massoth RJ, Teicher BA, Downey EM, Nelson AC: A low frequency imaging electron spin resonance spectrometer for non-invasive measurement of tumor oxygenation and other parameters characterizing tumor radiosensitivity. Int J Radiat Oncol Biol Phys 12(Suppl I): 117–118, 1986
Grunewald WA, Leubers DW: Cryophotometry as a method for analyzing intracapillary HbO2 saturation of organs under different O2 supply conditions. Adv Exp Med Biol 75: 55–64, 1976
Mueller-Klieser W, Vaupel P, Manz R: Tumor oxygenation under normoxic and hyperbaric conditions. Brit J Radiol 56: 559–564, 1983
Vaupel P, Manz R, Mueller-Klieser W, Grunewald WA: Intracapillary HbO2 saturation in malignant tumors during normoxia and hyperoxia. Microvasc Res 17: 181–191, 1979
Shipley WU, Stanley JA, Steel GG: Tumor size dependency in the radiation response of the Lewis lung carcinoma. Cancer Res 35: 2488–2493, 1975
Stanley JA, Shipley WU, Steel GG: Influence of tumour size on hypoxic fraction and therapeutic sensitivity of Lewis lung tumour. Brit J Cancer 36: 105–113, 1977
Jirtle R, Clifton KH: The effect of tumor size and host anemia on tumor cell survival after irradiation. Int J Radiat Oncol Biol Phys 4: 395–400, 1978
Hill RP: An appraisal of in vitro assays of excised tumours. Brit J Cancer 41(Suppl IV): 230–239, 1980
Hill RP, Stanley JA: The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents. Cancer Res 35: 1147–1153, 1975
Stanley JA, Peckham MJ, Steel GG: Influence of tumour size on radiosensitization by misonidazole. Brit J Cancer 37(Suppl III): 220–224, 1978
Suit H, Maeda M: Oxygen effect factor and tumor volume in the C3H mouse mammary carcinoma. Amer J Roent 96: 177–182, 1966
Siemann DW: Tumor size: A factor influencing the isoeffect analysis of tumor response to combined modalities. Brit J Cancer 41(Suppl IV): 294–298, 1980
Suit H, Lindberg R, Suchato C, Ozenne A: Radiation dose fractionation and high pressure oxygen in radiotherapy of the DBA mouse mammary carcinoma. Amer J Roent 99: 895–899, 1966
Thrall DE, Gillette EL, Dewey WC: Effect of heat and ionizing radiation on normal and neoplastic tissue of the C3H mouse. Radiat Res 63: 363–377, 1975
Denekamp J, Harris SR: Tests of two electron-affinic radiosensitizers in vivo using regrowth of an experimental carcinoma. Radiat Res 61: 191–203, 1975
Sheldon PW, Hill SA: Further investigations of the effects of the hypoxic-cell radiosensitizer, Ro-07–0582, on local control of a mouse tumour. Brit J Cancer 36: 198–205, 1977
Rice L, Urano M, Suit HD: The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays. Brit J Cancer 41(Suppl IV): 240–244, 1980
Brown JM, Twentyman PR, Zamvill SS: Response of the RIF-1 tumor in vitro and in C3H/Km mice to X-radiation (cell survival, regrowth delay, and tumor control), chemotherapeutic agents, and activated macrophages. J Nat Cancer Inst 64: 606–611, 1980
Urano M, Koike S: Comparison of the effects of neutron and/or photon irradiation on spontaneous squamous-cell carcinoma in mice. Radiology 134: 219–225, 1980
VanPutten LM, DeRuiter J, VanderVecht B: Reoxygenation between radiotherapy fractions in an experimental osteosarcoma. Europ J Cancer Clin Oncol 21: 1561–1562, 1985
Hewitt HB, Wilson CW: A survival curve for mammalian leukaemia cells irradiated in vivo (implications for treatment of mouse leukaemia by whole-body irradiation). Brit J Cancer 13: 69–75, 1959
Hewitt HB, Wilson CW: The effect of tissue oxygen tension on the radiosensitivity of leukaemia cells irradiated in situ in the livers of leukaemic mice. Brit J Cancer 13: 675–684, 1959
Siemann DW, Kochanski K: Combinations of radiation and misonidazole in a murine lung tumor model. Radiat Res 86: 387–397, 1981
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Moulder, J.E., Rockwell, S. Tumor hypoxia: its impact on cancer therapy. Cancer Metast Rev 5, 313–341 (1987). https://doi.org/10.1007/BF00055376
Issue Date:
DOI: https://doi.org/10.1007/BF00055376