The significance of vascular targeting agents as chemotherapeutic drugs for controlling solid tumors.

• Project/Area Number: 16591204
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Radiation science
• Research Institution: Research Reactor Institute, Kyoto University
• Principal Investigator: MASUNAGA Shin-ichiro Kyoto Univ., Res.Reactor Inst., Associate Professor, 原子炉実験所, 助教授 (80238914)
• Co-Investigator(Kenkyū-buntansha): SAKURAI Yoshinori Kyoto Univ., Res.Reactor Inst., Assistant Professor, 原子炉実験所, 助手 (20273534)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
• Keywords: Vascular targeting agent / Bioreductive agent / Neutron capture therapy / p53 Status / Hypoxic cell fraction / Acutely hypoxic fraction / Chronically hypoxic fraction / Continuous administration / 低酸素細胞毒 / 休止期腫瘍細胞 / 分割照射 / 微小核 / アポトーシス

Research Abstract

The effects of a vascular targeting agent (VTA), ZD6126, on quiescent (Q) cell populations in solid tumors including in combination with radiation exposure or conventional anticancer chemotherapy were evaluated in terms of the micronucleus (MN) frequency and the surviving fraction, using our own method for selectively detecting the Q cell response to DNA-damaging treatment.
Combination with ZD6126 was regarded as more promising in borocaptate-^<10>B (BSH)-boron neutron capture therapy (BNCT) than L-para-boronophenylalanine-^<10>B (BPA)-BNCT, and more effective for enhancing the sensitivity of the Q tumor cells than that of the total tumor cells. This resulted in the decrease in the extended difference in the sensitivity between the total and Q tumor cells caused by the use of ^<10>B-carrier for BNCT.
The significant enhancive effect by ZD6126 combined with hypoxic cytotoxin was irrespective of p53 status, and slightly greater for total than Q cells. In the treatment of conventional cancer therapy resistant Q tumor cells or p53-mutated tumor cells, the use of hypoxic cytotoxin was very promising either alone or when VTA was co-administered.
Continuous administration of hypoxic cytotoxin elevated the sensitivity of both total and Q cells, especially total cells. It was probably because continuous administration of hypoxic cytotoxin could make it possible to kill acutely hypoxic tumor cells efficiently. Mild temperature hyperthermia (MTH) raised the sensitivity of Q cells more remarkably than that of total cells. It was thought to be probably because of the higher dose distribution of hypoxic cytotoxin in intermediately hypoxic areas derived mainly from chronic hypoxia through MTH. From the viewpoint of tumor control as a whole including both total and Q tumor cells, the continuous administration of hypoxic cytotoxin combined with MTH may be useful for sensitizing tumor cells in vivo.

Research Products

• [Journal Article] Evaluation of Hypoxia-Specific Cytotoxic Bioreductive Agent-Sodium Borocaptate-^<10>B Conjugates, as ^<10>B-Carriers in Boron Neutron Capture Therapy. (2006)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Radiation Medicine 24・2 Pages: 98-107
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Evaluation of hypoxic cell radio-sensitizers in terms of radio-sensitizing and repair-inhibiting potential --- with reference to the dependency on p53 status of tumor cells and the effects on intratumor quiescent cells. (2006)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Anticancer Research 26 Pages: 1261-1270
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented ^<10>B conjugate compound, TX-2100, for boron neutron capture therapy. (2006)
  • Author(s): Masunaga S, Nagasawa H, Sakurai Y, et al.
  • Journal Title: International Journal of Hyperthermia 22・4 Pages: 287-299
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Evaluation of Hypoxia-Specific Cytotoxic Bioreductive Agent-Sodium Borocaptate-^<10>B Conjugates, as ^<10>B-Carriers in Boron Neutron Capture Therapy. (2006)
  • Author(s): Masunaga S, Nagasawa H, Gotoh K, Sakurai Y, Uto Y, Hori H, Nagata K, Suzuki M, Maruhashi A, Kinashi Y, Ono K.
  • Journal Title: Radiation Medicine 24(2) Pages: 98-107
  • NAID: 10020572481
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evaluation of hypoxic cell radio-sensitizers in terms of radio-sensitizing and repair-inhibiting potential ---with reference to the dependency on p53 status of tumor cells and the effects on intratumor quiescent cells. (2006)
  • Author(s): Masunaga S.Nagasawa H, Uto Y, Hori H, Nagata K, Suzuki M, Kinashi Y, Ono K.
  • Journal Title: Anticancer Research 26 Pages: 1261-1270
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented ^<10>B conjugate compound, TX-2100, for boron neutron capture therapy. (2006)
  • Author(s): Masunaga S, Nagasawa H, Sakurai Y, Uto Y, Hori H, Nagata K, Suzuki M, Maruhashi A, Kinashi Y, Ono K
  • Journal Title: International Journal of Hyperthermia 22(4) Pages: 287-299
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evaluation of Hypoxia-Specific Cytotoxic Bioreductive Agent-Sodium Borocaptate-10B Conjugates, as 10B-Carriers in Boron Neutron Capture Therapy. (2006)
  • Author(s): Masunaga S, Nagasawa H, Gotoh K, Sakurai Y, Uto Y, Hori H, Nagata K, Suzuki M, Maruhashi A, Kinashi Y, Ono K..
  • Journal Title: Radiation Medicfine 24(2) Pages: 98-107
  • NAID: 10020572481
• [Journal Article] Evaluation of hypoxic cell radio-sensitizers in terms of radio-sensitizing and repair-inhibiting potential - with reference to the dependency on p53 status of tumor cells and the effects on intratumor quiescent cells. (2006)
  • Author(s): Masunaga S, Nagasawa H, Uto Y, Hori H, Nagata K, Suzuki M, Kinashi Y, Ono K.
  • Journal Title: Anticancer Research 26 Pages: 1261-1270
• [Journal Article] The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumor cell populations. (2005)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: International Journal of Hyperthermia 21・4 Pages: 305-318
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on the quiescent tumor cells and the dependency on p53 status of tumor cells. (2005)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Oncology Reports 14・2 Pages: 393-400
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on the quiescent tumor cells and the dependency on p53 status of tumor cells. (2005)
  • Author(s): Masunaga S, Nagasawa H, Uto Y, Hori H, Ohnishi K, Takahashi A, Ohnishi T, Suzuki M, Nagata K, Kinashi Y, Ono K.
  • Journal Title: Oncology Reports 14(2) Pages: 393-400
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumor cell populations (2005)
  • Author(s): Masunaga S, Nagasawa H, Uto Y, Hori H, Suzuki M, Nagata K, Kinashi Y, Ono K.
  • Journal Title: International Journal of Hyperthermia 21(4) Pages: 305-318
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on the quiescent tumor cells and the dependency on p53 status of tumor cells. (2005)
  • Author(s): Masunaga S, Nagasawa H, Uto Y, Honi H, Ohnishi K, Takahashi A, Ohnishi T, Suzuki M, Nagata K, Kinashi Y, Ono K.
  • Journal Title: Oncology Report 14(2) Pages: 393-400
• [Journal Article] The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumor cell populations. (2005)
  • Author(s): Masunaga S, Nagasawa H, Uto Y, Honi H, Suzuki M, Nagata K, Kinashi Y, Ono K.
  • Journal Title: International Journal of Hyperthermia 21(4) Pages: 305-318
• [Journal Article] Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms : an efficacy study based on findings on neuroimages. (2005)
  • Author(s): Miyatake, S., Kawabata, S., Kajimoto, Y., Aoki, A., Yokoyama, K., Yamada, M., Kuroiwa, T., Tsuji, M., Imahori, Y., Kirihata, M., Sakurai, Y., Masunaga, S., Nagata, K., Maruhashi, A., Ono, K.
  • Journal Title: Journal of Neurooncology 103(6) Pages: 1000-1009
• [Journal Article] Applicability of combination with the vascular targeting agent ZD6126 in boron neutron capture therapy. (2004)
  • Author(s): Masunaga S, Sakurai Y, et al.
  • Journal Title: Intetnational Journal of Radiation Oncology Biology Physics 60・3 Pages: 920-927
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of mild temperature hyperthermia and p53 status on the size of hypoxic fractions in solid tumors, with reference to the effect in intratumor quiescent cell populations. (2004)
  • Author(s): Masunaga S, Takahashi A, et al.
  • Journal Title: Intetnational Journal of Radiation Oncology Biology Physics 60・2 Pages: 570-577
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of mild temperature hyperthermia and p53 status on the size of hypoxic fractions in solid tumors, with reference to the effect in intratumor quiescent cell populations. (2004)
  • Author(s): Masunaga S, Takahashi A, Ohnishi K, Ohnishi T, Nagata K, Suzuki M, Kinashi Y, Ono K.
  • Journal Title: International Journal of Radiation Oncology Biology Physics 60(2) Pages: 570-577
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Applicability of combination with the vascular targeting agent ZD6126 in boron neutron capture therapy. (2004)
  • Author(s): Masunaga S, Sakurai Y, Nagata K, Suzuki M, Maruhashi A, Kinashi Y, Ono K.
  • Journal Title: International Journal of Radiation Oncology Biology Physics 60(3) Pages: 920-927
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Applicability of combination with the vascular targeting agent ZD6126 in boron neutron capture therapy. (2004)
  • Author(s): Masunaga S, Sakurai Y, et al.
  • Journal Title: Int J Radiat Oncol Biol Phys 60・3 Pages: 920-927
• [Journal Article] Effects of mild temperature hyperthermia and p53 status on the size of hypoxic fractions in solid tumors, with reference to the effect in intratumor quiescent cell populations. (2004)
  • Author(s): Masunaga S, Takahashi A, et al.
  • Journal Title: Int J Radiat Oncol Biol Phys 60・2 Pages: 570-577
• [Journal Article] The usefulness of 2-nitroimidazole-^<10>B-carriers in boron neutron capture therapy (2004)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Journal of Applied Radiation and Isotopes 61 Pages: 953-958
• [Journal Article] Applicability of 2-nitroimidazole-sodium borocaptate-^<10>B conjugate, TX-2060, as a ^<10>B-carrier in boron neurton Capture therapy. (2004)
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Anticancer Research 24 Pages: 2975-2984
• [Journal Article] The usefulness of mild temperature hyperthermia combined with a newly developed hypoxia-oriented 10B conjugate compound, TX-2100, for boron neutron capture therapy.
  • Author(s): S Masunaga, H Nagasawa, Y Sakurai, Y Uto, H Hori, K Nagata, M Suzuki, ^* A Maruhashi, Y Kinashi, K Ono.
  • Journal Title: International Journal of Hyperthermia (in press)
• [Journal Article] The usefulness of continuous administration of hypoxic cytotoxin combined with mild temperature hyperthermia, with reference to effects on quiescent tumor cell populations.
  • Author(s): Masunaga S, Nagasawa H, et al.
  • Journal Title: Int J Hyperthermia (in press)