金沢大学医学部・附属病院
放射免疫療法の治療効果を予測する際,組織低酸素の有無や程度は重要な因子であるが,従来は確認が困難であった.また,種々の化学療怯やBMRを組み合わせる場合,腫瘍組織の低酸素は腫瘍血管新生のトリガーとなる.今年度は,組織の低酸素状態を評価するトレーサとして,4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione bisoxime(HL91)の特性評価を主にin vivoで行った.HL91はニトロイミダゾール基を持たず,Tc-99m標識化合物であることが特徴である.また,同時に血流指標のトレーサであるTl-201と比較検討した.主要細胞とのin vitro結合アッセイには,マウス単球性白血病細胞P388を用い,低酸素状態と大気中での有酸素状態での各トレーサの細胞への結合率を比較した.有酸素状態ではHL91のP388へ結合は低値を示した(2.4±0.11% at 20min,37±0.14% at 240min)が,低酸素状態ではTl-201の結合率が低下した180分以降に,HL91の結合率が上昇する現象が認泌られた(2.8±0.11% at 20min,40.4±091% at 240min).in vivoモデルには,マウス単球性白血病細胞P388とLewis Lung Cancer細胞を用いた.Lewis Lung Cancer細胞を移植したマウスを用いて経時的な体内分布を評価した.Tc-99m標識HL91は,投与早期に腫瘍へ高集積を示し,経時的には洗い出されるものの(3.72%ID/g, at 15min, 2.55 at 60min, 1.73 at 120min),バックグラウンド放射能はさらに速く消失した(4.47%ID/g, at 15min,1.12 at 60min,0.37 at 120min).Tl-201はバックグラウンド放射能が高値を持続したため,Tc-99m標識の方がTl-201よりも,良好な腫瘍集積性を示した.HL91は,Tl-201とは異なった動態を示すため,腫瘍診断において新たな情報を付加する可能性が期待できる.すなわちこのトレーサは,低酸素組織への親和性を示すため,放射線感受性の予想に利用できるのみならず,組織低酸素により誘発される血管新生および血行性転移の危険予知にも展開できる。
Objectives: Hypoxia is known to increase resistance to radiation therapy. Moreover, hypoxia induced after certain anticancer drugs initiates neoangiogenesis in tumor tissues resulting in the first step of distant metastases. Therefore, it is clinically important to assess tumor hypoxia as an indicator of radio- and chemotherapeutic effect as well as a prognosis factor. In hypoxic tissues, 4,9-diaza-3, 3, 10, 10-tetramethyl dodecan-2, 11-dione bisoxime (HL91) is designed to accumulate and retained. In this study, we have attempted to evaluate Tc-99m-HL91 as a tumor targeting agent comparing with Tl-201, a flow dependent tumor-seeking agent.Methods: P388 mouse leukemia, Lewis lung cancer (LLC) and B-16 melanoma cells were used either for in vitro cell binding assay (CBA) or pharmakokinetic studies in tumor xenografted mouse models. CBA was performed under hypoxic condition and compared to normoxic incubation. The biodistribution was assessed at 15, 60, 120 and 180 min after administration of Tc-99m-HL91 and Tl-201. Imaging studies were also performed with both tracers.Results: Under normoxic condition %binding to P388 of Tc-99m-HL91 was low throughout the study (2.4 ± 0.11 % at 20 min and 3.7 ± 0.14% at 240 min), whereas under hypoxic condition %binding was increased with time (2.8 ± 0.11 % at 20 min and 40.4 ± 0.91% at 240 min). The biodistribution study showed comparable tumor uptake to B-16 between both tracers (HL91: 3.1% at 15 min, 2.7% at 180 min vs. Tl-201: 2.5%, 3.2%, respectively). However, the background activity of Tc-99m HL91 is lower than Tl-201 (muscle: HL91: 3.2% at 15 min, 0.8% at 180 min vs. Tl-201: 4.9%, 7.0%, respectively). The transplanted LLC and B-16 tumors were clearly visible with Tc-99m-HL91 and distribution pattern in the tumor was discordant with Tl-201.Conclusion: Tc-99m-HL91 preferentially accumulates into hypoxic cells and is not flow dependent. Therefore, Tc-99m-HL91 can be used to detect tumor localization and provide the information on status of tumor hypoxia, which is distinctively different from Tl-201.
研究課題/領域番号:10670838, 研究期間(年度):1998 – 2000
出典：「微小転移および不顕性転移に対するアイソトープ標識抗体の抗腫瘍効果の増幅」研究成果報告書 課題番号10670838（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （ https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-10670838/ ）を加工して作成