Skip to main content
SpringerLink
Log in

Optimised Treatment Modalities for Hypoxic Tumour Cells

  • Conference paper
Drug Delivery in Cancer Treatment II

Part of the book series: ESO Monographs ((ESO MONOGRAPHS))

Abstract

Solid tumours are made up of many different cell types, including heterogeneous neoplastic subpopulations. The targeting of therapeutic strategies to particular cell populations within tumours has therefore a sound rational basis. Considerable evidence supports the existence of hypoxic cells in solid tumours, and their role in limiting response to radiotherapy and chemotherapy [1,2].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Coleman CN: Hypoxia in tumours: a paradigm for the approach to biochemical and physiologic heterogeneity. J Natl Cancer Inst 1988 (80): 310–317

    Article  PubMed  CAS  Google Scholar 

  2. Coleman CN: Chemical modification of radiation and chemotherapy. In De Vita V T Jr, Hellman S and Rosenberg S A (eds) Cancer: Principles and Practises of Oncology. Lippincott, Philadelphia (in press)

    Google Scholar 

  3. Thomlinson RH and Gray LH: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955 (9): 539–549

    Article  PubMed  CAS  Google Scholar 

  4. Chaplin DJ, Olive PL and Durand RE: Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res 1987 (47): 597–601

    PubMed  CAS  Google Scholar 

  5. Hall EH: Radiobiology for the Radiologist. New York, Harper and Row, 1978

    Google Scholar 

  6. Workman P: New drugs against hypoxic cells. Cancer Topics 1983 (4): 54–55

    Google Scholar 

  7. Heacock CS and Sutherland RM: Induction characteristics of oxygen regulated proteins. Int J Radiat Oncol Biol Phys 1986 (12): 1287–1290

    Article  PubMed  CAS  Google Scholar 

  8. Rice GC, Hou CA and Schimke RT: Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 1986 (83): 5978–5982

    Article  PubMed  CAS  Google Scholar 

  9. Chapman JD: The detection and measurement of hypoxic cells in solid tumours. Cancer 1984 (54): 2441–2449

    Article  PubMed  CAS  Google Scholar 

  10. Franko AJ: Misonidazole and other hypoxia markers: metabolism and applications. Int J Radiat Oncol Biol Phys 1986 (12): 1195–1202

    Article  PubMed  CAS  Google Scholar 

  11. Horowitz M, Blasberg R, Molnar P, Strong J, Kornblith P, Pleasants R and Fenstermacher J: Regional (14C) misonidazole distribution in experimental RT-9 brain tumors. Cancer Res 1983 (43): 3800–3807

    PubMed  CAS  Google Scholar 

  12. Urtasun RC, Chapman JD, Raleigh JA, Franko AJ and Koch CJ: Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia. Int J Radiat Oncol Biol Phys 1986 (12): 1263–1267

    Article  PubMed  CAS  Google Scholar 

  13. Raleigh JA, Miller GG, Franko AJ, Koch CJ, Fuciarelli AF and Kelly DA: Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. Br J Cancer 1987 (56): 395–400

    Google Scholar 

  14. Raleigh JA, Franko AJ, Treiber EO, Lunt JA and Allen PS: Covalent binding of a fluorinated 2- nitroimidazole to EMT6 tumors in BALB/c mice: Detection by F-19 magnetic resonance at 2.35 T. Int J Radiat Oncol Biol Phys 1986 (12): 1243–1245

    Article  PubMed  CAS  Google Scholar 

  15. Maxwell RJ, Workman P and Griffiths JR: Demonstration of tumor-selective retention of fluorinated nitroimidazole probes by magnetic resonance spectroscopy in vivo. Int J Radiat Oncol Biol Phys (in press)

    Google Scholar 

  16. Dische S: Chemical sensitizers for hypoxic cells: A decade of experience in clinical radiotherapy. Radiother Oncol 1985 (3): 97–115

    Article  PubMed  CAS  Google Scholar 

  17. Wasserman TH: Hypoxic cell radiosensitizers: Illusion or elusion? Int J Radiat Oncol Biol Phys 1988 (15): 779–781

    Article  PubMed  CAS  Google Scholar 

  18. Workman P: Development of nitroimidazoles. In: Davis W, Maltoni C, Tanneberger SE (eds) The Control of Tumour Growth and its Biological Bases. Springer-Verlag, Berlin, 1983, pp 166–172

    Google Scholar 

  19. Workman P: Accelerated elimination of pimonidazole in mice: A possible approach to reduced neurotoxicity of the pimonidazole-etanidazole combination. Int J Radiat Oncol Biol Phys (in press)

    Google Scholar 

  20. Brown JM and Workman P: Paritition coefficient as a guide to the development of radiosensitizers which are less toxic than misonidazole. Rad Res 1980 (82): 171–190

    Article  CAS  Google Scholar 

  21. Newman HFV, Bleehen NM, Ward R and Workman P.:Hypoxic cell radiosensitezers in the treatment of high grade gliomas: a new direction using combined Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole). Int J Radiat Oncol Biol Phys 1988 (15): 677–684

    Article  PubMed  CAS  Google Scholar 

  22. Coleman CN, Halsey J, Cox RS, Hirst K, Blaske T, Howes AE, Wasserman TH, Urtasun RC, Pajak T, Hancock S, Phillips TL and Noll L: Relationship between the neurotoxicity of the hypoxic cell radiosenstizer SR 2508 and the pharmacokinetic profile. Cancer Res 1987 (47): 319–322

    PubMed  CAS  Google Scholar 

  23. Dennis MF, Stratford MRL, Wardman P, Watts ME: Cellular uptake of misonidazole and analogues with acidic or basic functions. Int J Radiat Biol 1985 (47): 629–643

    Article  CAS  Google Scholar 

  24. Dische S, Saunders MI, Bennet MH, Dunphy EP, Des Rochers C, Stratford MRL, Minchingon AI and Wardman P: A comparison of the tumour concentrations obtainable with misonidazole and Ro 03-8799. Br J Radiol 1986 (59): 911–917

    Article  PubMed  CAS  Google Scholar 

  25. Stratford MRL, Dennis MF, Watts ME and Watfa RR: Radiosensitizer-DNA interactions. Br J Radiol 1988 (61): 861–862

    Article  Google Scholar 

  26. Roberts JT, Bleehen NM, Walton MI, and Workman P: A clinical phase I toxicity study of Ro 03-8799: plasma, urine, tumour and normal brain pharmacokinetics. Br J Radiol 1986 (59): 107–116

    Article  PubMed  CAS  Google Scholar 

  27. Saunders MI, Anderson PJ, Bennet MH, Dische S, Minchinton A, Stratford MRL and Tothill M: The clinical testing of Ro 03-8799 - pharmacokinetics, toxicology, tissue and tumour concentrations. Int J Radiat Oncol Biol Phys 1984 (10): 1759–1763

    Article  PubMed  CAS  Google Scholar 

  28. Honess DJ, Wasserman TH, Workman P, Ward R and Bleehen N M: Additivity of radiosensitization by the combination of SR 2508 (etanidazole) and Ro 03- 8799 (pimonidazole) in a murine tumour system. Int J Radiat Oncol Biol Phys 1988 (15): 671–675

    Article  PubMed  CAS  Google Scholar 

  29. Bleehen NM, Newman HFV, Maughan TS and Workman P: A multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole). Int J Radiat Oncol Biol Phys (in press)

    Google Scholar 

  30. Adams GE, Ahmed I, Sheldon PW and Stratford U: RSU 1069, a 2-nitroimidazole containg an alkylating group: high efficiency as a radio- and chemosensitizer in vitro and in vivo. Int J Radiat Oncol Biol Phys 1984 (10): 1653–1656

    Article  PubMed  CAS  Google Scholar 

  31. Walton MI and Workman P: Pharmacokinetics and metabolism of the mixed-function hypoxic cell sensitizer prototype RSU 1069 in mice. Cancer Chemother Pharmacol 1988 (22): 275–281

    Article  PubMed  CAS  Google Scholar 

  32. Horwich A, Holliday SB, Deacon JM and Peckham MJ: A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitizer RSU 1069. Br J Radiol 1986 (59): 1238–1240

    Article  PubMed  CAS  Google Scholar 

  33. Sieman DW: Modification of chemotherapy by nitroimidazoles. Int J Radiat Oncol Biol Phys 1984 (10): 1585–1594

    Article  Google Scholar 

  34. Mulcahy RT and Trump DL: Clinical chemosensitization by misonidazole and related compounds: a critical evaluation. J Clin Oncol 1988 (6): 569–573

    PubMed  CAS  Google Scholar 

  35. Workman P: Chemosensitization of lomustine by misonidazole, benznidazole and RSU 1069. Cancer Treat Rep 1986 (70): 1139–1141

    PubMed  CAS  Google Scholar 

  36. Roberts JT, Bleehen NM, Lee FYF, Workman P and Walton MI: A phase I study of the combination of benznidazole and CCNU in man. Int J Radiat Oncol Biol Phys 1984 (10): 1745–1748

    Article  PubMed  CAS  Google Scholar 

  37. Bleehen N M, Roberts J T and Newman H F V: A phase II study of CCNU with benznidazole for metastatic malignant melanoma. Int J Rad Oncol Biol Phys 1986 (12): 1401–1403

    Article  CAS  Google Scholar 

  38. Bleehen NM, Freedman L and Stenning S: Phase III study of CCNU with or without benznidazole for recurrent gliomas. Int J Radiat Oncol Biol Phys (in press)

    Google Scholar 

  39. Coleman CN, Carlson RC, Halsey J, Kohler M, Gribble M, Sikic BI and Jacobs C: Enhancement of the clinical activity of melphalan by the hypoxic cell sensitizer misonidazole. Cancer Res 1988 (48): 3528–3532

    PubMed  CAS  Google Scholar 

  40. Coleman CN, Bump EA and Kramer RA: Chemical modifiers of cancer treatment. J Clin Oncol 1988 (6): 709–733

    PubMed  CAS  Google Scholar 

  41. Lee FYF and Workman P: Modification of CCNU pharmacokinetics by misonidazole. A major mechanism of chemosensitization. Br J Cancer 1983 (47): 659–669

    Article  PubMed  CAS  Google Scholar 

  42. Lee FYF and Workman P: Misonidazole and CCNU: Further evidence for a pharmacokinetic mechanism of chemosensitization and therapeutic gain. Br J Cancer 1984 (49): 579–585

    Article  PubMed  CAS  Google Scholar 

  43. Lee FYF and Workman P: Misonidazole protects mouse tumour and normal tissues from the toxicity of oral CCNU. Br J Cancer 1985 (51): 85–91

    Article  PubMed  CAS  Google Scholar 

  44. Lee FYF, Workman P and Cheeseman KH: Misonidazole and benznidazole inhibit hydroxylation of CCNU by mouse liver microsomal cytochrome P- 450 in vitro. Biochem Pharmac 1987 (36): 1349–1355

    Article  CAS  Google Scholar 

  45. Workman P, Lee FYF, Walton MI, Roberts JT and Bleehen NM: Nitroimidazole inhibition of mouse and human cytochrome P-450 mediated hydroxylation of the chloroethylnitrosourea, CCNU. In: Benford DJ, Bridges JW and Gibson GG (eds) Drug Metabolism - from Molecules to Man. Taybr and Francis, London, 1987 pp 303–308

    Google Scholar 

  46. Hinchcliffe M, McNally NJ and Stratford MRL: The effect of radiosensitizers on the pharmacokinetics of melphalan and cyclosphosphamide in the mouse. Br J Cancer 1983 (48): 375–383

    Article  Google Scholar 

  47. Randhawa VS, Stewart FA, Denekamp J and Stratford MRL: Factors influencing the chemosensitization of melphalan by misonidazole. Br J Cancer 1985 (51): 219–228

    Article  PubMed  CAS  Google Scholar 

  48. Horsman MR, Evans JW and Brown JM: Enhancement of melphalan-induced tumour cell killing by misonidazole: An interaction of competing mechanisms. Br J Cancer 1984 (50): 305–316

    Article  PubMed  CAS  Google Scholar 

  49. Murray JC, Randhawa V and Denekamp J: The effects of melphalan and misonidazole on the vasculature of a murine sarcoma. Br J Cancer 1987 (55): 233–238

    Article  PubMed  CAS  Google Scholar 

  50. Lee FYF and Workman P: Nitroimidazoles as modifiers of nitrosourea pharmacokinetics. Int J Radiat Oncol Biol Phys 1984 (10): 1627–1630

    Article  PubMed  CAS  Google Scholar 

  51. Kennedy KA: Hypoxic cells as specific drug targets for chemotherapy. Anticancer Drug Design 1987 (2): 181–194

    CAS  Google Scholar 

  52. Zeman EM, Brown JM, Lemmon MJ, Hirst VK and Lee WW: SR 4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells. Int J Radiat Oncol Biol Phys 1986 (12): 1239–1242

    Article  PubMed  CAS  Google Scholar 

  53. Hewick DS: Reductive metabolism of nitrogen-containing functional groups. In: Jakoby WB, Bend JR, Caldwell J (eds) Metabolic Basis of Detoxication: Metabolism of Functional Groups. Academic Press, New York, 1982

    Google Scholar 

  54. Walton MI and Workman P: Nitroimidazole reductive metabolism: Quantitation and characterization of mouse tissue benznidazole nitroreductases in vivo and in vitro. Biochem Pharmac 1987 (36): 887–896

    Article  CAS  Google Scholar 

  55. Walton MI, Wolf CR and Workman P: Molecular enzymology of the reductive bioactivation of hypoxic cell cytotoxins. Int J Radiat Oncol Biol Phys (in press)

    Google Scholar 

  56. Heimbrook DC and Sartorelli AC: Biochemistry of misonidazole reduction by NADPH-cytochrome c (P-450) reductase. Mol Pharmac 1986 (29): 168–172

    CAS  Google Scholar 

  57. Knox RJ, Friedlos F, Roberts JJ: The activation of CB 1954 (2, 4-dinitro-5-aziridinyl benzamide) in Walker cells is by bioreduction to DNA crosslinking agent. Br J Cancer 1988 (58): 252

    Google Scholar 

  58. Walton MI and Workman P: Pharmacokinetics and bioreductive metabolism of the benztriazine-di-N- oxide hypoxic cell cytotoxin SR 4233 in mice. Cancer Res (submitted)

    Google Scholar 

  59. Laderoute KR and Rauth AM: Identification of two major reduction products of the hypoxic cell toxin 3- amino-1,2,4-benzotriazine-1,4-dioxide. Biochem Pharmac 1986 (35): 3417–3420

    Article  CAS  Google Scholar 

  60. Laderoute K, Wardman P and Rauth AM: Molecular mechanisms for the hypoxia-dependent activation of 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233). Biochem Pharmac 1988 (37): 1487–1495

    Article  CAS  Google Scholar 

  61. Powis G, Hodnett EM, Santone KS, Lee See K and Melder DC: Role of metabolism and oxidation reduction cycling in the cytotoxicity of antitumour quinoneimines and quinonediimines. Cancer Res 1987 (22): 2363–2370

    Google Scholar 

  62. Bachur NR, Gordon SL, Gee MV and Kon H: NADPH- cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci USA 1979 (76): 954–957

    Article  PubMed  CAS  Google Scholar 

  63. Tomasz M, Lipman R, Chowdary D, Pawlak J, Verdine GL and Nakanishi K: Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science 1987 (235): 1204–1208

    Article  PubMed  CAS  Google Scholar 

  64. Vingen BA and Powis G.: Pulse radiolysis of anticancer quinones: radical life times, reactivity with oxygen and one-electron reduction potentials. Arch Biochem Biophys 1981 (209): 119–126

    Article  Google Scholar 

  65. Keyes SR, Fracasso PM, Heimbrook DC, Rockwell S, Sligar SG and Sartorelli AC: Role of NADPH- cytochrome C reductase and DT-diaphorase in the biotransformation of mitomycin C. Cancer Res 1984 (44): 5638–5643

    PubMed  CAS  Google Scholar 

  66. Keyes SR, Rockwell S and Sartorelli AC: Enhancement of mitomycin C cytotoxicity to hypoxic tumor cells by dicoumarol in vivo and in vitro. Cancer Res 1985 (45): 213–216

    PubMed  CAS  Google Scholar 

  67. Schlager JJ and Powis G: Mitomycin C is not metabolised by but is an inhibitor of human kidney NAD(P)H: (quinone-acceptor) oxidoreductase. Cancer Chemother Pharmacol 1988 (22): 126–130

    Article  PubMed  CAS  Google Scholar 

  68. Fracasso PM and Sartorelli AC: Cytotoxicity and DNA lesions produced by mitomycin C and porfiromycin in hypoxic and aerobic EMT6 and Chinese hamster ovary cells. Cancer Res 1986 (46) 3939–3944

    PubMed  CAS  Google Scholar 

  69. Chakrabarty S, Danels YJ, Long BH, Willson JKV and Brattain MG: Circumvention of deficient activation in mitomycin C-resistant human colonic carcinoma cells by the mitomycin C analogue BMY 25282. Cancer Res 1986 (46): 3456–3458

    PubMed  CAS  Google Scholar 

  70. Kooistra KL and Workman P: Analysis and preclinical pharmacology of the indoloquinone E0.9. Cancer Chemother Pharmacol (submitted)

    Google Scholar 

  71. Powis G: Anthracycline metabolism and free radical formation. In: Powis G and Prough R A (eds) Metabolism and Action of Anticancer Drugs. Taylor and Francis, London, 1987, pp 211–295

    Google Scholar 

  72. Walton MI, Bleehen NM and Workman P: Heat- stimulated nitroreductive bioactivation of the 2- nitroimidazole benznidazole in vitro. Biochem Pharmacol 1987 (36): 2627–2632

    Article  PubMed  CAS  Google Scholar 

  73. Walton MI, Bleehen NM and Workman P: Stimulation by localised tumour hyperthermia of the nitroreductive bioactivation of the 2-nitroimidazole benznidazole in mice. Cancer Res (in press)

    Google Scholar 

  74. Brown JM: Exploitation of bioreductive agents with vasoactive drugs. In: Fielden EM, Fowler JF, Hendry JH and Scott D (eds) Radiation Research. Taylor and Francis, London, 1987 pp 719–724

    Google Scholar 

  75. Stratford U, Adams GE, Godden J, Nolan J, Howells N and Timpson N: Potentiation of the anti-tumour effect of melphalan by the vasoactive agent, hydralazine. Br J Cancer 1988 (58): 122–127

    Article  PubMed  CAS  Google Scholar 

  76. Evetoch JL, Bissery MC, Chabot GG, Simpson NE, McCoy CL, Heibrun LK and Corbett TH: Flavone acetic acid (NSC 347512)-induced modulation of murine tumour physiology monitored by in vivo nuclear magnetic resonance spectroscopy. Cancer Res 1988 (48): 4749–4755

    Google Scholar 

  77. Adams GE, Barnes DWH, du Boulay C, Loutit JF, Cole S, Sheldon PW, Stratford IJ, van den Aardweg GJMJ, Hopewell JW, White RD, Kneen G, Nethersell AB and Edwards JC: Induction of hypoxia in normal and malignant tissues by changing the oxygen affinity of hemoglobin-implications for therapy. Int J Radiat Oncol Biol Phys 1986 (12): 1299–1302

    Article  PubMed  CAS  Google Scholar 

  78. Hirst DG, Hazlehurst JL and Brown JM: The effect of hematocrit on tumour sensitivity to X-rays. Int J Rad Biol 1984 (46): 345–354

    Article  CAS  Google Scholar 

  79. Kinsella TJ, Dobson PP, Russo A, Mitchell JB and Fornace AJ: Modulation of X-ray DNA damage by SR 2508 with or without buthionine sulfoximine. Int J Radiat Oncol Biol Phys 1986 (12): 1127–1130

    Article  PubMed  CAS  Google Scholar 

  80. Phillips TL, Mitchell JB, De Graff W, Russo A and Glatstein E: Variation in sensitizing efficiency for SR 2508 in human cells dependent on glutathione content. Int J Radiat Oncol Biol Phys 1986 (12): 1627–1635

    Article  PubMed  CAS  Google Scholar 

  81. Rice GC, Bump EA, Shrieve DC, Lee W and Kovacs M: Quantitative analysis of cellular glutathione in Chines hamster ovary cells by flow cytometry utilizing monochlorobimane: Some applications to radiation and drug resistance in vitro and in vivo. Cancer Res 1986 (46): 6105–6110

    PubMed  CAS  Google Scholar 

  82. Workman P and Watson JV: Flow cytoenzymology of glutathione metabolism. Cytometry 1987 (Suppl 1 ): 270

    Google Scholar 

  83. Workman P, Cox H and Watson JV: Glutathione metabolism in human lymphocytes by flow cytometry. Cytometry 1988 (Suppl 2 ): 47

    Google Scholar 

  84. Begg AC, Hodgkiss RJ, McNally NJ, Middleton RW, Stratford MRL and Terry NHA: Fluorescent markers for hypoxic cells: A comparison of two compounds on three cell lines. Br J Radiol 1985 (58): 645–654

    Article  PubMed  CAS  Google Scholar 

  85. Begg AC, Engelhardt EL, Hodgkiss RJ, McNally NJ, Terry NHA and Wardman P: Nitroakridin 3582: A fluorescent nitroacridine stain for identifying hypoxic cells. Br J Radiol 1983 (56): 970–973

    Article  PubMed  CAS  Google Scholar 

  86. Chaplin DJ, Durand RE and Olive PL: Cell selection from a murine tumour using the fluorescent probe Hoechst 33342. Br J Cancer 1985 (51): 569–572

    Article  PubMed  CAS  Google Scholar 

  87. Olive PL, Chaplin DJ and Durand RE: Pharmacokinetics, binding and distribution of Hoechst 33342 in spheroids and murine tumours. Br J Cancer 1985 (52): 739–746

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Hills Road, Cambridge, UK

    P. Workman

Authors
  1. P. Workman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Surgery, Regional Hospital, 70185, Örebro, Sweden

    Lennart Domellöf

Rights and permissions

Reprints and permissions

Copyright information

© 1989 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Workman, P. (1989). Optimised Treatment Modalities for Hypoxic Tumour Cells. In: Domellöf, L. (eds) Drug Delivery in Cancer Treatment II. ESO Monographs. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74709-0_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-74709-0_7

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-74711-3

  • Online ISBN: 978-3-642-74709-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation