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. 1999 Feb;79(5-6):814–820. doi: 10.1038/sj.bjc.6690130

RSR13, an allosteric effector of haemoglobin, and carbogen radiosensitize FSAII and SCCVII tumours in C3H mice

S R Khandelwal 1, B D Kavanagh 1, P-S Lin 1, Q T Truong 1, J Lu 1, D J Abraham* 1, R K Schmidt-Ullrich 1
PMCID: PMC2362693  PMID: 10070874

Abstract

Pre-clinical evaluation has demonstrated that 2-[4-(((3,5-dimethylanilino)carbonyl)methyl)phenoxy]-2-methylpropionic acid (RSR13) acts as an allosteric effector of haemoglobin (Hb). RSR13 binding to Hb results in decreased haemoglobin–oxygen (Hb–O2) affinity, improved tumour oxygenation, and enhanced radiation-induced cell killing in several experimental tumour systems. In the present work, ex vivo clonogenic survival analyses are applied in two murine tumour systems to characterize the relationship between the magnitude of decrease in Hb–O2 affinity and radiosensitization, the influence of inspired pO2 upon this effect, and the efficacy of combining RSR13 and radiation during a course of repeated radiation exposures. For FSaII tumours in C3H mice breathing air, 100 mg kg−1 RSR13 administered intraperitoneally produced an enhancement ratio (ER) of 1.3, but there was marked desensitization at a RSR13 dose of 300 mg kg−1 (ER 0.6). The most likely reason for the increased radioresistance was insufficient oxygen loading of Hb in the pulmonary circulation due to reduced haemoglobin–oxygen affinity because carbogen breathing combined with 300 mg kg−1 RSR13 reversed the effect and produced an ER of 1.8. In SCCVII tumours in C3H mice irradiated with eight fractions of 2.5 Gy over 4 days, the surviving fraction was reduced to 58–67% of control values when RSR13 was combined with radiation on days 1 and 2, days 3 and 4, or days 1–4. These results confirm that combining RSR13 and irradiation within a fractionated course of clinically relevant low-dose exposures provides significant radiosensitization. Additional preclinical experimentation is needed to define better the optimum dose-scheduling conditions for clinical applications. 1999 Cancer Research Campaign

Keywords: RSR13, haemoglobin–oxygen affinity, allosteric effectors of haemoglobin, tumour hypoxia, radiosensitizer

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Selected References

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  1. Abraham D. J., Peascoe R. A., Randad R. S., Panikker J. X-ray diffraction study of di and tetra-ligated T-state hemoglobin from high salt crystals. J Mol Biol. 1992 Sep 20;227(2):480–492. doi: 10.1016/0022-2836(92)90902-v. [DOI] [PubMed] [Google Scholar]
  2. Abraham D. J., Wireko F. C., Randad R. S., Poyart C., Kister J., Bohn B., Liard J. F., Kunert M. P. Allosteric modifiers of hemoglobin: 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats. Biochemistry. 1992 Sep 29;31(38):9141–9149. doi: 10.1021/bi00153a005. [DOI] [PubMed] [Google Scholar]
  3. Brady L. W., Plenk H. P., Hanley J. A., Glassburn J. R., Kramer S., Parker R. G. Hyperbaric oxygen therapy for carcinoma of the cervix--stages IIB, IIIA, IIIB and IVA: results of a randomized study by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 1981 Aug;7(8):991–998. doi: 10.1016/0360-3016(81)90149-8. [DOI] [PubMed] [Google Scholar]
  4. Brizel D. M., Sibley G. S., Prosnitz L. R., Scher R. L., Dewhirst M. W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997 May 1;38(2):285–289. doi: 10.1016/s0360-3016(97)00101-6. [DOI] [PubMed] [Google Scholar]
  5. Brown J. M., Lemmon M. J. Potentiation by the hypoxic cytotoxin SR 4233 of cell killing produced by fractionated irradiation of mouse tumors. Cancer Res. 1990 Dec 15;50(24):7745–7749. [PubMed] [Google Scholar]
  6. Bush R. S., Jenkin R. D., Allt W. E., Beale F. A., Bean H., Dembo A. J., Pringle J. F. Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer Suppl. 1978 Jun;3:302–306. [PMC free article] [PubMed] [Google Scholar]
  7. Dewhirst M. W., Ong E. T., Rosner G. L., Rehmus S. W., Shan S., Braun R. D., Brizel D. M., Secomb T. W. Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content. Br J Cancer Suppl. 1996 Jul;27:S241–S246. [PMC free article] [PubMed] [Google Scholar]
  8. Dische S., Anderson P. J., Sealy R., Watson E. R. Carcinoma of the cervix--anaemia, radiotherapy and hyperbaric oxygen. Br J Radiol. 1983 Apr;56(664):251–255. doi: 10.1259/0007-1285-56-664-251. [DOI] [PubMed] [Google Scholar]
  9. Dorie M. J., Menke D., Brown J. M. Comparison of the enhancement of tumor responses to fractionated irradiation by SR 4233 (tirapazamine) and by nicotinamide with carbogen. Int J Radiat Oncol Biol Phys. 1994 Jan 1;28(1):145–150. doi: 10.1016/0360-3016(94)90152-x. [DOI] [PubMed] [Google Scholar]
  10. EVANS J. C., BERGSJO P. THE INFLUENCE OF ANEMIA ON THE RESULTS OF RADIOTHERAPY IN CARCINOMA OF THE CERVIX. Radiology. 1965 Apr;84:709–717. doi: 10.1148/84.4.709. [DOI] [PubMed] [Google Scholar]
  11. Fletcher G. H., Lindberg R. D., Caderao J. B., Wharton J. T. Hyperbaric oxygen as a radiotherapeutic adjuvant in advanced cancer of the uterine cervix: preliminary results of a randomized trial. Cancer. 1977 Feb;39(2):617–623. doi: 10.1002/1097-0142(197702)39:2<617::aid-cncr2820390237>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  12. Gatenby R. A., Kessler H. B., Rosenblum J. S., Coia L. R., Moldofsky P. J., Hartz W. H., Broder G. J. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys. 1988 May;14(5):831–838. doi: 10.1016/0360-3016(88)90002-8. [DOI] [PubMed] [Google Scholar]
  13. Gerweck L. E., Koutcher J. A., Zaidi S. T., Seneviratne T. Energy status in the murine FSaII and MCaIV tumors under aerobic and hypoxic conditions: an in-vivo and in-vitro analysis. Int J Radiat Oncol Biol Phys. 1992;23(3):557–561. doi: 10.1016/0360-3016(92)90011-6. [DOI] [PubMed] [Google Scholar]
  14. Goda F., O'Hara J. A., Rhodes E. S., Liu K. J., Dunn J. F., Bacic G., Swartz H. M. Changes of oxygen tension in experimental tumors after a single dose of X-ray irradiation. Cancer Res. 1995 Jun 1;55(11):2249–2252. [PubMed] [Google Scholar]
  15. Hirst D. G., Wood P. J. Chlorophenoxy acetic acid derivatives as hemoglobin modifiers and tumor radiosensitizers. Int J Radiat Oncol Biol Phys. 1989 May;16(5):1183–1186. doi: 10.1016/0360-3016(89)90279-4. [DOI] [PubMed] [Google Scholar]
  16. Hirst D. G., Wood P. J., Schwartz H. C. The modification of hemoglobin affinity for oxygen and tumor radiosensitivity by antilipidemic drugs. Radiat Res. 1987 Oct;112(1):164–172. [PubMed] [Google Scholar]
  17. Hirst D. G., Wood P. J. The influence of haemoglobin affinity for oxygen on tumour radiosensitivity. Br J Cancer. 1987 May;55(5):487–491. doi: 10.1038/bjc.1987.99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Horsman M. R., Chaplin D. J., Overgaard J. The use of blood flow modifiers to improve the treatment response of solid tumors. Radiother Oncol. 1991;20 (Suppl 1):47–52. doi: 10.1016/0167-8140(91)90187-l. [DOI] [PubMed] [Google Scholar]
  19. Horsman M. R., Khalil A. A., Siemann D. W., Grau C., Hill S. A., Lynch E. M., Chaplin D. J., Overgaard J. Relationship between radiobiological hypoxia in tumors and electrode measurements of tumor oxygenation. Int J Radiat Oncol Biol Phys. 1994 Jun 15;29(3):439–442. doi: 10.1016/0360-3016(94)90434-0. [DOI] [PubMed] [Google Scholar]
  20. Höckel M., Knoop C., Schlenger K., Vorndran B., Baussmann E., Mitze M., Knapstein P. G., Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993 Jan;26(1):45–50. doi: 10.1016/0167-8140(93)90025-4. [DOI] [PubMed] [Google Scholar]
  21. Jain R. K. Determinants of tumor blood flow: a review. Cancer Res. 1988 May 15;48(10):2641–2658. [PubMed] [Google Scholar]
  22. Khandelwal S. R., Randad R. S., Lin P. S., Meng H., Pittman R. N., Kontos H. A., Choi S. C., Abraham D. J., Schmidt-Ullrich R. Enhanced oxygenation in vivo by allosteric inhibitors of hemoglobin saturation. Am J Physiol. 1993 Oct;265(4 Pt 2):H1450–H1453. doi: 10.1152/ajpheart.1993.265.4.H1450. [DOI] [PubMed] [Google Scholar]
  23. Moulder J. E., Rockwell S. Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys. 1984 May;10(5):695–712. doi: 10.1016/0360-3016(84)90301-8. [DOI] [PubMed] [Google Scholar]
  24. Nordsmark M., Høyer M., Keller J., Nielsen O. S., Jensen O. M., Overgaard J. The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 1996 Jul 1;35(4):701–708. doi: 10.1016/0360-3016(96)00132-0. [DOI] [PubMed] [Google Scholar]
  25. Nordsmark M., Overgaard M., Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996 Oct;41(1):31–39. doi: 10.1016/s0167-8140(96)91811-3. [DOI] [PubMed] [Google Scholar]
  26. Okunieff P. G., Koutcher J. A., Gerweck L., McFarland E., Hitzig B., Urano M., Brady T., Neuringer L., Suit H. D. Tumor size dependent changes in a murine fibrosarcoma: use of in vivo 31P NMR for non-invasive evaluation of tumor metabolic status. Int J Radiat Oncol Biol Phys. 1986 May;12(5):793–799. doi: 10.1016/0360-3016(86)90038-6. [DOI] [PubMed] [Google Scholar]
  27. Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6(10-11):509–518. [PubMed] [Google Scholar]
  28. Overgaard J., Hansen H. S., Andersen A. P., Hjelm-Hansen M., Jørgensen K., Sandberg E., Berthelsen A., Hammer R., Pedersen M. Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study. Int J Radiat Oncol Biol Phys. 1989 Apr;16(4):1065–1068. doi: 10.1016/0360-3016(89)90917-6. [DOI] [PubMed] [Google Scholar]
  29. Randad R. S., Mahran M. A., Mehanna A. S., Abraham D. J. Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents. J Med Chem. 1991 Feb;34(2):752–757. doi: 10.1021/jm00106a041. [DOI] [PubMed] [Google Scholar]
  30. Rice L., Urano M., Suit H. D. The radiosensitivity of a murine fibrosarcoma as measured by three cell survival assays. Br J Cancer Suppl. 1980 Apr;4:240–244. [PMC free article] [PubMed] [Google Scholar]
  31. Siemann D. W., Hill R. P., Bush R. S., Chhabra P. The in vivo radiation response of an experimental tumor: the effect of exposing tumor-bearing mice to a reduced oxygen environment prior to but not during irradiation. Int J Radiat Oncol Biol Phys. 1979 Jan;5(1):61–68. doi: 10.1016/0360-3016(79)90039-7. [DOI] [PubMed] [Google Scholar]
  32. Siemann D. W., Macler L. M. Tumor radiosensitization through reductions in hemoglobin affinity. Int J Radiat Oncol Biol Phys. 1986 Aug;12(8):1295–1297. doi: 10.1016/0360-3016(86)90157-4. [DOI] [PubMed] [Google Scholar]
  33. Van Putten L. M., Kallman R. F. Oxygenation status of a transplantable tumor during fractionated radiation therapy. J Natl Cancer Inst. 1968 Mar;40(3):441–451. [PubMed] [Google Scholar]
  34. Ward A. J., Dixon B. Carcinoma of the cervix: results of a hyperbaric oxygen trial associated with the use of the cathetron. Clin Radiol. 1979 Jul;30(4):383–387. doi: 10.1016/s0009-9260(79)80213-5. [DOI] [PubMed] [Google Scholar]
  35. Wireko F. C., Kellogg G. E., Abraham D. J. Allosteric modifiers of hemoglobin. 2. Crystallographically determined binding sites and hydrophobic binding/interaction analysis of novel hemoglobin oxygen effectors. J Med Chem. 1991 Feb;34(2):758–767. doi: 10.1021/jm00106a042. [DOI] [PubMed] [Google Scholar]

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