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Implantable biodegradable polymers for IUdR radiosensitization of experimental human malignant glioma

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Abstract

Purpose: The potential of halogenated pyrimidines for the radiosensitization of human malignant gliomas remains unrealized. To assess the role of local delivery for radiosensitization, we tested a synthetic, implantablebiodegradable polymer for the controlled release of 5-iodo-2‘-deoxyuridine (IUdR) both in vitro and in vivo and the resultant radiosensitizationof human malignant glioma xenografts in vivo.Materials and methods: In vitro: To measure release, increasing (10%, 30%, 50%) proportions (weight/weight) of IUdR in the polyanhydride [(poly(bis(p-carboxyphenoxy)-propane) (PCPP) :sebacic acid (SA) (PCPP : SA ratio 20 : 80)] polymer discs were incubated (1 ml phosphate-buffered saline, 37° C). The supernatant fractions were serially assayed using high performance liquid chromatography. To measure modulation of release,polymer discs were co-loaded with 20 μCi 5-125-iodo-2‘-deoxyuridine (125-IUdR) and increasing (10%, 30%, or 50%) proportions of D-glucose. To test radiosensitization, cells (U251 human malignant glioma) were sequentially exposed to increasing (0 or 10 μM) concentrations of IUdR and increasing (0, 2.5, 5.0, or 10 Gy) doses of acute radiation. In vivo: To measure release, PCPP : SA polymerdiscs having 200 μCi 125-IUdR were surgically placed in U251 xenografts (0.1—0.2 cc) growing in the flanksof nude mice. The flanks were reproducibly positioned over a collimated scintillation detector and counted. To measure radiosensitization, PCPP : SApolymer discs having 0% (empty) or 50% IUdR wereplaced in the tumor or contralateral flank. After five days, the tumors were acutely irradiated (500 cGy × 2 daily fractions).Results: In vitro: Intact IUdR was released from the PCPP : SA polymer discs in proportion to the percentage loading. After 4 days the cumulative percentages of loaded IUdR that were released were 43.7 $plusmn; 0.1, 70.0 ± 0.2, and 90.2 ± 0.2 (p < 0.001 ANOVA) for the 10, 30, and 50% loadings. With 0, 10, 30,or 50% D-glucose co-loading, the cumulative release of 125-IUdR from PCPP : SA polymers was 21, 70, 92, or 97%(p < 0.001), respectively, measured 26 days after incubation.IUdR radiosensitized U251 cells in vitro. Cell survival (log10) was – 2.02 ± 0.02 and – 3.68± 0.11 (p < 0.001) after the 10 Gy treatment and no (control) or 10 μM IUdR exposures, respectively. In vivo: 125-IUdR Release: The average counts (log10 cpm ± SEM) (hours after implant) were 5.2 ± 0.05 (0.5), 4.3 ± 0.07 (17), 3.9 ± 0.08 (64), and 2.8 ± 0.06 (284). Radiosensitization: Afterintratumoral implantation of empty polymer or intratumoral 50%IUdR polymer, or implantation of 50% IUdR polymers contralateral to tumors, the average growth delays of tumors to4 times the initial volumes were 15.4 ± 1.8, 20.1 + 0.1,and 20.3 + 3.6 (mean + SEM) days, respectively (p = 0.488one-way ANOVA). After empty polymer and radiation treatments,no tumors regressed and the growth delay was 31.1 + 2.1 (p = 0.046 vs. empty polymer alone) days. After implantation of50% IUdR polymers either contralateral to the tumors orinside the tumors, followed by radiation, tumors regressed; growth delays to return to the initial average volumes of 14.0+ 3.6 or 24.2 + 0.2 (p < 0.01) days, respectively.Conclusions: Synthetic, implantable biodegradable polymers hold promise for the controlled release and local delivery ofIUdR for radiosensitization of gliomas.

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References

  1. Kornblith PL, Walker M: Chemotherapy for malignant gliomas. J Neurosurg 68: 1–17, 1988

    PubMed  Google Scholar 

  2. Chang C, Horton J, Schoenfeld D, Salazar O, Perez-Tamayo R, Kramer S, Weinstein A, Nelson J, Tsjkada Y: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint radiation therapy oncology group and eastern cooperative oncology group study. Cancer 52(6): 997–1007, 1983

    PubMed  Google Scholar 

  3. Walker MD, Strike TA, Sheline GE: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 49: 333–343, 1978

    PubMed  Google Scholar 

  4. Walker MD, Strike TA, Sheline GE: An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5: 1725–1731, 1979

    PubMed  Google Scholar 

  5. Curran WJ, Scott CB, Nelson JS: Survival comparison of radiosurgery eligible and ineligible malignant glioma patients treated with hyperfractionated radiation therapy and BCNU: A report of RTOG 83-02. J Clin Oncol 11: 857–862, 1993

    PubMed  Google Scholar 

  6. Simpson JR, Horton J, Scott C, Curran WJ, Rubin P, Fischbach J, Isaacson S, Rotman M, Asbell S, Nelson J, Weinstein A, Nelson D: Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive radiation therapy oncology group (RTOG) clinical trials. Int J Radiat Oncol Biol Phys 26: 239–244, 1993

    PubMed  Google Scholar 

  7. Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30: 907–911, 1980

    Google Scholar 

  8. Bashir R, Hochberg F, Oot R: Regrowth patterns of glioblastoma multiforme related to planning of interstitial brachytherapy radiaton fields. Neurosurgery 23: 27–30, 1988

    PubMed  Google Scholar 

  9. Wallner K, Galicich J, Krol G, Arbit E, Malkin M: Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16: 1405–1409, 1989

    PubMed  Google Scholar 

  10. Uhl V, Phillips T, Ross G, Bodell W, Rasmussen J: Iododeoxyuridine incorporation and radiosensitization in three human tumor cell lines. Int J Radiat Oncol Biol Phys 22: 489–494, 1992

    PubMed  Google Scholar 

  11. McLaughlin PW, Lawrence TS, Seabury H, Nguyen N, Stetson PL, Greenberg HS, Mancini WR: Bromodeoxyuridinemediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation. Int J Radiat Oncol Biol Phys 30(3): 601–607, 1994

    PubMed  Google Scholar 

  12. Erickson R, Szybalski W: Molecular radiobiology of human cell lines. V. Comparative radiosensitizing properties of 5-halodeoxycytidines and 5-halodeoxyuridines. Radiat Res 20: 252–262, 1963

    PubMed  Google Scholar 

  13. Fornace AJ, Dobson PP, Kinsella TJ: Enhancement of radiation damage in cellular DNA following unifilar substitution with iododeoxyuridine. Int J Radiat Oncol, Biol Phys 18: 873–878, 1990

    Google Scholar 

  14. Uhl V, Phillips T, Ross G, Bodell W, Rasmussen J: Iododeoxyuridine incorporation and radiosensitization in three human tumor cell lines. Int J Radiat Oncol, Biol Phys 22: 489–494, 1992

    Google Scholar 

  15. Levin VA, Prados MR, Wara WM, Davis RL, Gutin PH, Phillips TL, Lamborn K, Wilson CB: Radiation therapy and bromodeoxyuridine chemotherapy followed by procarbazine, lomustine, and vincristine for the treatment of anaplastic gliomas. Int J Radiat Oncol Biol Phys 32(1): 75–83, 1995

    Article  Google Scholar 

  16. Djordjevic B, Szybalsi W: Genetics of human cell lines. III. Incorporation of 5-bromo-and 5-iododeoxyuridine into deoxyribonucleic acid of human cells and its effect on radiation sensitivity. J Exp Med 112: 509–531, 1960

    Article  PubMed  Google Scholar 

  17. Erickson R, Szybalski W: Molecular radiobiology of human cell lines. V. Comparative radiosensitizing properties of 5-halodeoxycytidines and 5-halodeoxyuridines. Radiat Res 20: 252–262, 1963

    PubMed  Google Scholar 

  18. Sano S, Hoshino T, Hagai M: Radiosensitization of brain tumor cells with a thymidine analog (bromouridine). J Neurosurg 28: 530–538, 1968

    PubMed  Google Scholar 

  19. Kinsella T, Collins J, Rowlan J, Klecker R, Wright D, Katz D, Steinberg S, Glatstein E: Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme. J Clin Oncol 6: 871–879, 1988

    PubMed  Google Scholar 

  20. Goffinet DR, Brown JM: Comparison of intravenous and intra-arterial pyrimidine infusion as a means of radiosensitizing tumors. Radiology 124: 819–822, 1977

    PubMed  Google Scholar 

  21. Russo A, Gianni L, Kinsella T, Klecker R, Jenkins J, Rowland J, Glatstein E, Mitchell M, Collins J, Myers C: Pharmacological evaluation of intravenous delivery of 5-bromodeoxyuridine to patients with brain tumors. Cancer Res 44: 702–1705, 1984

    Google Scholar 

  22. Jackson D, Kinsella TJ, Rowland J, Wright D, Katz D, Main D, Collins J, Kornblith P, Glatstein E: Halogenated pyrimidines as radiosensitizers in the treatment of glioblastoma multiforme. Am J Clin Oncol 10: 437–443, 1987

    PubMed  Google Scholar 

  23. Kinsella T, Russo A, Mitchell J, Collins J, Rowland J, Wright D, Glatstein EA: Phase I study of intravenous iododeoxyuridine as a clinical radiosensitizer. Int J Radiat Oncol Biol Phys 11: 1941–1946, 1985

    PubMed  Google Scholar 

  24. Kinsella T, Collins J, Rowlan J, Klecker R, Wright D, Katz D, Steinberg S, Glatstein E: Pharmacology and phase I/II study of continuous intravenous infusions of iododeoxyuridine and hyperfractionated radiotherapy in patients with glioblastoma multiforme. J Clin Oncol 6: 871–879, 1988

    PubMed  Google Scholar 

  25. Greenberg HS, Chandler WF, Ensminger WD: Radiosensitization with carotid arterial infusion bromodeoxyuridine and external beam radiation for gliomas. In: Ensminger WD, Selam JL (eds) Update in Drug Delivery Systems, Mount Kisco, NY, Futura Publishing Co., 233–246, 1989

    Google Scholar 

  26. Hegarty TJ, Thornton AF, Diaz RF, Chandler WF, Ensigner WD, Junck L, Page MA, Gebarski SS, Hood TW, Stetson PL, Tankanow RM, McKevver PE, Lichter AS, Greenberg HS: Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas. Int J Radiat Oncol, Biol Phys 19: 421–428, 1990

    Google Scholar 

  27. Wirtanen GW, Wiley AL, Vermund H, Stephenson JA, Ansfield FJ: Intraarterial iododeoxyuridine infusion combined with irradiation. A pilot study. Am J Clin Oncol 13(4): 320–323, 1990

    PubMed  Google Scholar 

  28. Cook J, Glass J, Lebovics R, Bobo H, Pass H, Delaney T, Oldfield E, Mitchell J, Glatstein E, Goffman T: Measurement of thymidine replacement in patients with high grade gliomas, head and neck tumors, and high grade sarcomas after continuous intravenous infusion of 5-iododeoxyuridine. Cancer Res 52: 719–725, 1992

    PubMed  Google Scholar 

  29. Goffman TE, Dachowsk LJ, Bobo H, Oldfield E, Cook J, Mitchell JB, Katz D, Smith R, Glatstein E: Long-term follow-up on national cancer institute phase I/II study of glioblastoma multiforme treated with iododeoxyuridine and hyperfractionated irradiation. J Clin Oncol 10(2): 264–268, 1992

    PubMed  Google Scholar 

  30. Urtasun RC, Cosmatos D, DelRowe J, Kinsella TJ, Lester S, Wasserman T, Fulton DS: Iododeoxyuridine (IUdR) combined with radiation in the treatment of malignant glioma: A comparison of short versus long intravenous dose schedules (RTOG 86-12). Int J Radiat Oncol Biol Phys 27: 207–214, 1993

    PubMed  Google Scholar 

  31. Pollay M, Roberts PA: Blood-brain barrier: A definition of normal and altered function. Neurosurgery 6: 675–685, 1980

    PubMed  Google Scholar 

  32. Langer R, Wise D (eds): medical applications of controlled release. Boco Raton, Fla, CRC Press, 1986

    Google Scholar 

  33. Leong KW, D’Amore P, Marletta M, Langer R: Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity. J Biomed Mat Res 20: 51–64, 1986

    Google Scholar 

  34. Brem H, Mahaley S, Vick N, Black K, Schold C, Burger P, Friedman A, Ciric I, Eller T, Cozzens J, Kenealy J: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74:441–446, 1991

    PubMed  Google Scholar 

  35. Brem H, Piantadosi S, Burger P, Walker M, Selker R, Vick N, Black K, Sisti M, Brem S, Mohr G: Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345(8956): 1008–1012, 1995

    Article  Google Scholar 

  36. Domb A, Langer R: Polyanhydrides. I. Preparation of high molecular weight polyanhydrides. J Polymer Science 25: 3373–3386, 1987

    Google Scholar 

  37. Walter K, Cahan M, Gur A, Tyler B, Hilton J, Colvin O, Burger P, Domb A, Brem H: Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma. Cancer Res 54(8): 2207–2212, 1994

    PubMed  Google Scholar 

  38. Dillehay L, Mayer R, Zhang Y, Song S, Shao Y, Mackensen B, Williams J: Use of bremstrahlung radiation to monitor Y-90 tumor and whole body activities during experimental radioimmunotherapy in mice. Cancer 73(3) (suppl): 945–950, 1994

    PubMed  Google Scholar 

  39. Mayer R, Dillehay LE, Shao Y, Song S, Zhang Y, Bartholomew RM, Williams JR: A new method for determining dose rate distribution from radioimmunotherapy using radiochromic medium. Int J Radiat Oncol Biol Phys 28: 505–513, 1993

    Google Scholar 

  40. Williams JA, Klein JL, Wanek PM, Poggenburg KA, Wharam MD, Wessels BW, Order SE: Quantitative intercomparison of radiolabeled antibodies and external beam radiotherapy in the treatment of human glioma xenografts in vivo. Int J Radiat Oncol Biol Phys 24(1): 111–117, 1992

    PubMed  Google Scholar 

  41. Glantz SA: Primer of biostatistics. Pergamon Press, New York, 1992

    Google Scholar 

  42. Marin LA, Smith CE, Langston M, Quashie D, Dillehay L: Response of glioblastoma cell lines to low dose rate irradiation. Int J Radiat Oncol Biol Phys 21: 397–402, 1991

    PubMed  Google Scholar 

  43. McLaughlin PW, Mancini WR, Stetson PL, Greenberg HS, Nguyen N, Seabury H, Heidorn DB, Lawrence TS: Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma. Int J Radiat Oncol, Biol Phys 26: 637–642, 1993

    Google Scholar 

  44. McLaughlin PW, Mancini WR, Stetson PL, Greenberg HS, Nguyen N, Seabury H, Heidorn DB, Lawrence TS: Halogenated pyrimidine sensitization of low dose rate irradiation in human malignant glioma. Int J Radiat Oncol, Biol Phys 26: 637–642, 1993

    Google Scholar 

  45. Tamada J, Langer R: Erosion kinetics of hydrolytically degradable polymers. Proc Natl Acad Sci USA 90: 552–556, 1993

    PubMed  Google Scholar 

  46. Tabata Y, Domb A, Langer R: Injectable polyanhydride granules provide controlled release of water-soluble drugs with a reduced initial burst. J Pharm Sci 83: 5–11, 1994

    PubMed  Google Scholar 

  47. Tamada J, Langer R: The development of polyanhydrides for drug delivery applications. J Biomater Sci Polymer Edn 3(4): 315–353, 1992

    Google Scholar 

  48. McLaughlin PW, Lawrence TS, Seabury H, Nguyen N, Stetson PL, Greenberg HS, Mancini WR: Bromodeoxyuridine-mediated radiosensitization in human glioma: the effect of concentration, duration, and fluoropyrimidine modulation. Int J Radiat Oncol Biol Phys 30(3): 601–607, 1994

    PubMed  Google Scholar 

  49. Leong KW, Brott BC, Langer R: Bioerodible polyanhydrides as drug-carrier matrices. I. Characterization, degradation, and release characteristics. J Biomed Mater Res 19: 941–955, 1985

    PubMed  Google Scholar 

  50. Tjuvajev J, Muraki A, Ginos J, Berk J, Koutcher J, Ballon D, Beattie B, Finn R, Blasberg R: Iododeoxyuridine uptake and retention as measure of tumor growth. J Nucl Med 34 (7): 1152–1162, 1993

    PubMed  Google Scholar 

  51. Williams JA, Klein JL, Wanek PM, Poggenburg KA, Wharam MD, Wessels BW, Order SE: Quantitative intercomparison of radiolabeled antibodies and external beam radiotherapy in the treatment of human glioma xenografts in vivo. Int J Radiat Oncol Biol Phys 24(1): 111–117, 1992

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Radiobiology Laboratory, Division of Radiation Oncology, Department of Oncology, Johns Hopkins Oncology Center, 600 North Wolfe Street, Baltimore, MD, 21287-5001, USA

    Jeffery A. Williams, Larry E. Dillehay & Christian Fahlman

  2. Brain Tumor Research Laboratory, Department of Neurosurgery, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD, 21287-5001, USA

    Jeffery A. Williams, Kevin Tabassi, Eric Sipos & Henry Brem

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Williams, J.A., Dillehay, L.E., Tabassi, K. et al. Implantable biodegradable polymers for IUdR radiosensitization of experimental human malignant glioma. J Neurooncol 32, 181–192 (1997). https://doi.org/10.1023/A:1005704913330

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