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Relationship Between Drug Delivery and the Intra-arterial Infusion Rate of SarCNU in C6 Rat Brain Tumor Model

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Abstract

The influences of the flow rate on the concentration and distribution of drug in the rat brains and brain tumors after intra-arterial (intra-carotid) administration of [3H]SarCNU (sarcosinamide chloroethyl-1-nitrosourea) were examined. Results obtained at three flow rates via intra-carotid route were compared to those obtained with intravenous administrations. Adult female Wistar rats bearing C6 brain tumor were randomized into four-groups. Groups 1 (G.1) to 3 (G.3) received intra-arterial injection and Group 4 (G.4) received intravenous administration of [3H]SarCNU. G.1 (slow infusion rate) was administered 1 ml of [3H]SarCNU solution over 60 min (0.017 ml/min), Group 2 (G.2; medium infusion rate): 0.2 ml over 5 min (0.04 ml/min), G.3 (fast infusion rate): 1 ml over 5 min (0.2 ml/min), and G.4 (intravenous infusion): 1 ml intravenously over 5 min. Quantitative autoradiographic method was used to measure the concentration and the distribution of [3H]SarCNU in the brain and the brain tumors. The tissue uptake constant of SarCNU in both viable (tumor tissue excluding necrosis) and peak regions (the area of tumor containing top 20% of the tracer concentration) of the intra-arterial injection groups were significantly higher (p<0.0001) than those in the intravenous group. The mean concentrations of the viable tumor in the intra-arterial groups were 2.92 (G.1), 16.06 (G.2), and 20.8 (G.3) times higher than those of intravenous group. Between the intra-arterial groups, the mean concentration in the viable tumors of G.1 (slow flow rate) was significantly (p<0.0001) lower than in G.2 and G.3. However, there was no significant difference between G.2 and G.3. In three intra-arterial groups the mean concentration delivery ratios of the brain tumors were high and ranged from 3.07 (G.3) to 3.87 (G.2), but there was no significant difference between them. Only G.4, intravenous group, showed significantly (p<0.005) lower concentration delivery ratio, 1.26. These results suggest that higher infusion rate in the intra-arterial chemotherapy could have an effect not only on the streaming phenomenon which results in the brain toxicities, but also on the increase in the concentration and the sufficient distribution of a drug in tumors. By finding chemotherapeutic agents to which tumors show high sensitivity and using intra-arterial administration of these agents at more effective flow rate, better clinical results could be achieved in the treatment of patients with malignant brain tumors.

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References

  1. Shapiro WR, Byrne TN: Chemotherapy of brain tumor-basic concepts. In:Walker MD (ed) Oncology of the Nervous System. Martinus Nijhoff, Boston, 1983, pp 66–100

  2. Hochberg FH, Parker LM, Takvorian T, Canellos GP, Zervas NT: High dose BCNU with autologous bone marrow rescue for recurrent glioblastoma multiforme. J Neurosurg 54: 455–460, 1981

    PubMed  Google Scholar 

  3. Djerassi I, Jung SK, Reggev A: Response of astrocytoma to high-dose methotrexate with citrovorum factor rescue. Cancer 55: 2741–2747, 1985

    PubMed  Google Scholar 

  4. Fine HA, Aritman KH: High-dose chemotherapy with autologous bone marrow transplantation in the treatment of high grade astrocytomas in adults: therapeutic rationale and clinical experience. Bone Marrow Transplant10: 315–321, 1992

    PubMed  Google Scholar 

  5. Levin VA, Kabra PM, Freeman-Dove MA: Pharmacokinetics of intracarotid artery 14C-BCNU in the squirrel monkey. J Neurosurg48: 587–593, 1978

    PubMed  Google Scholar 

  6. Tyler JL, Yamamoto YL, Diksic M, Theron J, Villemure JG, Worthington C, Evans AC, Feindel W: Pharmacokinetics of superselective intra-arterial and intravenous 11C-BCNU evaluated by PET. J Nucl Med27: 775–778, 1986

    PubMed  Google Scholar 

  7. Echman WW, Patlak CS, Fenstermacher JD: A critical evaluation of the principles governing the advantages of intraarterial infusion. J Pharmacokinet Biopharm 2: 257–285, 1974

    PubMed  Google Scholar 

  8. Fenstermacher DE, Cowles AL: Theoretical limitations of intracarotid infusions in brain tumor chemotherapy. Cancer Treat Rep 61: 519–526, 1977

    PubMed  Google Scholar 

  9. Yamada K, Ushio Y, Hayakawa T, Arita N, Huang TY, Nagatani M, Yamada Y, Mogami H: Distribution of radiolabeled 1–(4–amino-2–methy1–5–pyrimidinyl)methyl-3–(2–chloroethyl)-3–nitrosourea hydrochloride in rat brain tumor: intra-arterial versus intravenous administration. Cancer Res 47: 2123–2128, 1987

    PubMed  Google Scholar 

  10. Schuster JM, Friedman HS, Archer GE, Fuchs HE, McLendon RE, Colvin OM, Bigner DD: Intra-arterial therapy of human glioma xenografts in athymic rats using 4–hydroperoxycyclophosphamide. Cancer Res 53: 2338–2343, 1993

    PubMed  Google Scholar 

  11. Hodozuka A, Sako K, Nakal H, Tomabechi M, Suzuki N, Yonemasu Y: Delivery of a novel nitrosourea, MCNU, to the brain tissue in glioma-bearing rats. Intracarotid versus intravenous infusion. J Neuro-Oncol 15: 79–86, 1993

    Google Scholar 

  12. Bullard DE, Bigner SH, Bigner DD: Comparison of intravenous versus intracarotid therapy with 1,3–bis(2–chloroethyl)-1–nitrosourea in a rat brain tumor model. Cancer Res. 45: 5240–5245, 1985

    PubMed  Google Scholar 

  13. Fauchon F, Davila L, Chatellier G, Fohanno D, Philippon J, Rey A, Chiras J, Poisson M, Delattre JY: Treatment of malignant gliomas with surgery, intra-arterial infusions of 1–(2–hydroxyethyl)chloroethylnitrosourea, and radiation therapy: a phase II study. Neurosurgery 27: 231–234, 1990

    PubMed  Google Scholar 

  14. Shapiro WR, Green SB, Burger PC, Selker PRG, Van Gilder JC, Robertson JT, Mealey Jr. J, Ransohoff J, Mahaley Jr. S: A randomized comparison of intra-arterial versus intravenous BCNU, with or without intravenous 5–fluorouracil, for newly diagnosed patients with malignant glioma. J Neurosurg 76: 772–781, 1992

    PubMed  Google Scholar 

  15. Saris SC, Blasberg RG, Carson RE, de Vroom HL, Lutz RJ, Dedrick RL, Pettigrew K, Chang R, Doppman J, Wright DC, Herscovitch P, Oldfield EH: Intravascular streaming during carotid artery infusions. J Neurosurg 74: 763–772, 1991

    PubMed  Google Scholar 

  16. Nagahiro S, Yamamoto YL, Diksic M, Mitsuka S, Sugimoto S, Feindel W: Neurotoxicity after intracarotid 1,3–bis(2–chloroethyl)-1–nitrosourea administration in the rat: hemodynamic changes studied by double-tracer autoradiography. Neurosurgery 29: 19–25, 1991

    PubMed  Google Scholar 

  17. Lutz RJ, Dedrick RL, Boretos JW, Oldfield EH, Blacklock JB, Doppman JL: Mixing studies during intracarotid artery infusion in an in vitro model. J Neurosurg 64: 277–283, 1986

    PubMed  Google Scholar 

  18. Blacklock JB, Wright DC, Dedrick RL, Blasberg RG, Lutz RJ, Doppman JL, Oldfield EH: Drug streaming during intraarterial chemotherapy. J Neurosurg 64: 284–291, 1986

    PubMed  Google Scholar 

  19. Greensberg HS, Ensminger WD, Chandler WF, Layton PB, Junck L, Knake J, Vine AK: Intra-arterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 61: 423–429, 1984

    PubMed  Google Scholar 

  20. Bobo H, Kapp JP, Vance R: Effect of intra-arterial cisplatin and 1,3–bis(2–chloroethyl)-1–nitrosourea (BCNU) dosage on radiographic response and regional toxicity in malignant glioma patients: proposal of a new method of intra-arterial dosage calculation. J Neuro-Oncol 13: 291–299, 1992

    Google Scholar 

  21. Hochberg FH, Pruitt AA, Beck DO, DeBrun G, Davis K: The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma. J Neurosurg 63: 876–880, 1985

    PubMed  Google Scholar 

  22. Mahaley Jr MS, Hipp SW, Dropcho EJ, Bertsch L, Cush S, Tirey T, Gillespie GY: Intracarotid cisplatin chemotherapy for recurrent gliomas. J Neurosurg 70: 371–378, 1989

    PubMed  Google Scholar 

  23. Madajewicz S, Chowhan N, Iliya A, Roque C, Beaton R, Davis R, Fertman S, Meek A, Alvares O, Pampati M, Tyson G: Intracarotid chemotherapy with etoposide and cisplatin for malignant brain tumors. Cancer 67:2844–2849, 1991

    PubMed  Google Scholar 

  24. Mortimer JE, Crowley J, Eyre H, Weiden P, Eltringham J, Struckey WJ: A phase II randomized study comparing sequential and combined intra-arterial cisplatin and radiation therapy in primary brain tumors. A Southwest Oncology Group Study. Cancer 69: 1220–1223, 1992

    PubMed  Google Scholar 

  25. DiChiro G, Oldfield EH, Wright DC: Cerebral necrosis after radiotherapy and/or intra-arterial chemotherapy for brain tumors: PET and neuropathologic studies. AINR 8: 1083–1091, 1987

    Google Scholar 

  26. Bashir R, Hochberg FH, Linggood RM, Hottleman K: Preirradiation internal carotid artery BCNU in treatment of glioblastoma multiforme. J Neurosurg 68: 917–919, 1988 246

    PubMed  Google Scholar 

  27. Johnson DW, Parkinson D, Wolpert SM, Kasdon DL, Kwan ESK, Laucella M, Anderson ML: Intracarotid chemotherapy with 1,3–bis(2–chloroethyl)-1–nitrosourea (BCNU) in 5% dextrose in water in the treatment of malignant glioma. Neurosurgery 20: 577–583, 1987

    PubMed  Google Scholar 

  28. Rogers LR, Purvis JB, Lederman RJ, Rosenbloom SA, Tomsak RL, Estes ML, Magdinec M, Medendorp SV, Boyett JM:Alternating sequential intracarotidBCNUand cisplatin in recurrent malignant glioma. Cancer 68: 15–21, 1991

    PubMed  Google Scholar 

  29. Suami T, Kato T, Takino H, Hisamatu T: (2–Chloroethyl)-nitrosourea congeners of amino acid amides. J Med Chem 25: 829–832, 1982

    PubMed  Google Scholar 

  30. Panasci LC, Dufour M, Chevalier L, Isabel G, Lazarus P, McQuillian A, Arbit E, Brem S, Feindel W: Utilization of HTSCA and CFV-C assay to identify two new 2–chloroethylnitrosourea congeners of amino acid amides with increased in vitro activity against human gliomas compared with BCNU. Cancer Chemo Pharm 14: 156–159, 1985

    Google Scholar 

  31. Houchens D, Nies R, Riblets S, Finfrok M, Trigg N: Immunodeficient animals in biochemical research. In: Wu BQ, Zheng J (eds) VI IntWorkshop on Immunodeficient Animals. Karger Publishing, Basel, Switzerland, 1989, pp 157–161

    Google Scholar 

  32. Mitsuki S, Diksic M, Conway T, Yamamoto YL, Villemure JG, Feindel W: Pharmacokinetics of 11C-labelled BCNU and SarCNU in gliomas studied by PET. J Neuro-Oncol 10: 47–55, 1991

    Google Scholar 

  33. Takeda N, Diksic M, Yamamoto YL: The sequential changes in DNA synthesis, glucose utilization, protein synthesis, and peripheral benzodiazepine receptor density in C6 brain tumors after chemotherapy to predict the response of tumors to chemotherapy. Cancer 77: 1167–1179, 1996

    PubMed  Google Scholar 

  34. Kurpad SN, Friedman HS, Archer GE, McLendon RE, Petros WM, Fuchs HE, Guaspari A, Bigner DD:Intra-arterial administration of melphalan for treatment of intracranial human xenografts in athymic rats. Cancer Research 55: 3803–3809, 1995

    PubMed  Google Scholar 

  35. Blasberg RG, Kobayashi bT, Patlak CS, Shinohara M, Miyoaka M, Rice JM, Shapiro WR: Regional blood flow, capillary permeability, and glucose utilization in two brain tumor models: preliminary observations and pharmacokinetic implications. Cancer Treat Report 65(Suppl. 2): 3–12, 1981

    Google Scholar 

  36. Mineura K, Sasajima T, Kowada M, Ogawa T, Hatazawa J, Shishido F, Uemura K: Perfusion and metabolism in predicting the survival of patients with cerebral gliomas. Cancer 73: 2386–2394, 1994

    PubMed  Google Scholar 

  37. Saris SC, Blasberg RG, Carson RE, deVroom HL, Lutz R, Dedrick RL, Pettigrew K, Chang R, Doppman J, Wright DC, Herscovitch P, Oldfield EH: Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration. J Neurosurg 74: 763–772, 1991

    PubMed  Google Scholar 

  38. Bloor BM, Glista GG: Observations on simultaneous internal carotid artery and total cerebral blood flow measurements in man. Neurosurgery 1: 249–255, 1977

    PubMed  Google Scholar 

  39. Uematsu S, Yang A, Preziosi TJ, Kouba R, Toung TJ: Measurement of carotid blood flow in man and its clinical application. Stroke 14: 256–266, 1983

    PubMed  Google Scholar 

  40. Weihe WH: The laboratory rat. In: Poole T (ed) The UFAW Handbook on The Care and Management of Laboratory Animals. Longman Scientific & Technical, Essex, 1987, pp 309–330

  41. Sakurada O, Kennedy C, Jehle J, Gwen JDB, Carbin GL, Sokoloff L: Measurement of local blood flow with iodo[14C]antipyrine. Am J Physiol234: H59–H66, 1978

    PubMed  Google Scholar 

  42. Watanabe A, Tanaka R, Takeda N, Washiyama K: DNA synthesis, blood flow, and glucose utilization in experimental rat brain tumors. J Neurosurg 70: 86–91, 1989

    PubMed  Google Scholar 

  43. Bullard DE, Saris SC, Bigner DD: Carotid artery injections in 40–to 99–g Fischer rats: Technical note and evaluation of blood flow by various injection techniques. Neurosurgery 14: 406–411, 1984

    PubMed  Google Scholar 

  44. Watne K, Hannisdal E, Nome O, Hager B, Hirschberg H: Combined intra-arterial and systemic chemotherapy for recurrent malignant brain tumor.Neurosurgery 30: 223–227, 1992

    PubMed  Google Scholar 

  45. Stewart DJ, Grahovac Z, Hugenholtz H, DaSilva V, Richard MT, Benoit B, Belanger G, Russel N: Feasibility study of intra-arterial vs intravenous cisplatin, BCNU, and toniposide combined with systemic cisplatin, teniposide, cytosine arabinoside, glycerol and mannitol in the treatment of primary and metastatic brain tumors. J Neuro-Oncol 17: 71–79, 1993

    Google Scholar 

  46. Shook DR, Beaudet LM, Doppman JL: Uniformity of intracarotid drug distribution with diastole-phased pulsed infusion. J Neurosurg 67: 726–731, 1987

    PubMed  Google Scholar 

  47. Aoki S, Terada H, Kosuda S, Shitara N, Fujii H, Suzuki K, Kutsukake Y, Tanaka J, Sasaki Y, Okubo T, Shirouzu I, Machida T, Sasaki Y: Supraophthalmic chemotherapy with long tapered catheter: distribution evaluated with intraarterial and intravenous Tc-99m. Radiology 188: 347–350, 1993

    PubMed  Google Scholar 

  48. Li JKJ: Laminar and turbulent flow in the mammalian aorta: Reynolds number. J Theor Biol 135: 409–414, 1988

    PubMed  Google Scholar 

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  1. Norio Takeda

    Present address: Department of Neurosurgery, Yamagata Prefectural Central Hospital, Yamagata, Japan

Authors and Affiliations

  1. Cone Laboratory for Neurosurgical Research, Montreal Neurological Institute, Canada

    Norio Takeda & Mirko Diksic

  2. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

    Norio Takeda

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  1. Norio Takeda
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  2. Mirko Diksic
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Takeda, N., Diksic, M. Relationship Between Drug Delivery and the Intra-arterial Infusion Rate of SarCNU in C6 Rat Brain Tumor Model. J Neurooncol 41, 235–246 (1999). https://doi.org/10.1023/A:1006104220315

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