延續探討本實驗室之前的研究，以VX2細胞誘發多發病灶肝腫瘤兔模式，探討以硼酸為含硼藥物進行硼中子捕獲治療 (Boron neutron capture therapy, BNCT) 之劑量評估與療效。本實驗使用3至5月齡、體重介於2.5至3.5公斤之雄性紐西蘭大白兔，進行VX2肝臟接種。藉由調整接種方式與接種位置，以降低早期遠端轉移之機率且控制腫瘤治療深度不超過3.5公分。為評估療效將荷多發病灶肝腫瘤兔 (n=1) 分為四組，分別為腫瘤控制組 (n=3)、中子照射組 (n=3)、一次BNCT治療組 (n=7) 與二次BNCT治療組 (n=2)。參考實驗室之前試驗結果，治療組之荷肝腫瘤兔經耳靜脈一次性注射300 mg/kg bw之硼酸 (等同於50 mg 10B/kg bw)，施藥後30分鐘在清華開放式水池反應器進行中子照射，搭配開口直徑為5.5公分之準直儀。一次BNCT治療組之腫瘤物理劑量範圍為6.88 0.37至12.81 0.00 Gy，一次治療後19天，多數腫瘤生長受到抑制 (10/11=90.90%)，而少數腫瘤體積呈現再增大 (復發) 現象。二次BNCT治療組之腫瘤於第一次BNCT治療所接受之物理劑量範圍為8.35 0.00至10.55 0.24 Gy，第一次治療後19天 (相當於第二次治療前1天)，經超音波與電腦斷層檢查，顯示多數腫瘤體積縮小 (4/5=80.00%)，周圍血流明顯減少，而少數體積再增大，且周圍伴隨新生血管。一次治療後20天進行第二次BNCT治療，腫瘤之物理劑量範圍為6.10 0.11至9.47 0.33 Gy，二次治療後5天，腫瘤持續縮小；二次治療後12天，血流已難以偵測，由影像學檢查顯示BNCT治療組經過治療後具有明顯療效。而腫瘤控制組及中子照射組則於VX2腫瘤接種後30至70天，因腫瘤嚴重侵犯至鄰近肝葉，且伴隨遠端肺轉移，而進行人道犧牲。荷肝腫瘤兔經BNCT治療後，常見皮膚發紅、輕微腹瀉及食慾不振導致體重下降等副作用，於治療後7至10天體重會逐漸恢復。整體而言，93.75% (=15/16) 的腫瘤經過BNCT治療後，腫瘤生長明顯受到抑制，於一次BNCT治療後180天或二次BNCT治療後180天，病理組織學檢查顯示荷肝腫瘤兔之病灶處已無殘存腫瘤細胞，且鄰近病灶處之肝臟細胞無發現異常變化。本實驗證實以硼酸為含硼藥物進行BNCT多發性肝癌治療，可在免除正常肝臟細胞受到傷害的條件下，選擇性殺傷腫瘤細胞及其血管，達到完全治癒之療效。因此，硼中子捕獲治療可視為一個比較理想的肝癌治療方式。
關鍵字：硼中子捕獲治療、硼酸、多發病灶肝腫瘤、兔VX2肝腫瘤模式

Following the preliminary research that was carried out at our laboratory, this study evaluates the optimal treatment dose and therapeutic efficacy of boric acid-mediated boron neutron capture therapy (BNCT) for liver cancer in a multifocal hepatic VX2 tumor-bearing rabbit model. Three-to-five-month-old male New Zealand White rabbits (2.5–3.5 kg) were used. VX2 carcinoma cells were implanted into the liver. The position of inoculation was varied and the depth of tumor cell implantation was controlled to be not more than 3.5 cm to prevent early distant metastasis. Fifteen multifocal liver tumor-bearing rabbits were divided into four groups, which were the tumor control group (n=3), the group that was treated with neutron beams only (n=3), the one-fraction BNCT-treated group (n=7), and the two-fraction BNCT-treated group (n=2). The rabbits in the latter two groups were injected with a 300 mg/kg bw bolus of BA solution (equal to 50 mg 10B/kg bw) into a marginal ear vein and, 30 minutes later, underwent neutron irradiation at the Tsing Hua Open Pool Reactor (THOR). A collimator with an aperture with a diameter of 5.5 cm was used. The physical dose that was administered in single-fraction BA-mediated BNCT ranged from 6.88 0.37 to 12.81 0.00 Gy. The inhibition of tumor growth was observed in most tumors following the BNCT treatment. However, some tumor recurrence was observed on the 19th day following the BNCT treatment. In the two-fraction BNCT-treated group, the physical doses that were delivered to tumors by the first and second fractions of BNCT ranged from 8.35 0.00 to 10.55 0.24 Gy and 6.10 0.11 to 9.47 0.33 Gy, respectively. For most tumors, an obvious reduction of size and blood flow around the tumor were detected by ultrasound scanning and computed tomography (CT) scanning 19 days after the first fraction of BNCT treatment (that was relative to 1 day before the second BNCT). The volume of only one tumor increased and new blood vessels developed around the tumor. The second BNCT treatment was performed on the 20th day after the first BNCT treatment. The size of the tumor continued to decrease thereafter and the blood flow around the tumor was undetectable 12 days after the second BNCT. The significant therapeutic response that was detected by ultrasound scanning was consistent with the results of the CT scanning. Owing to overgrowth of the tumor, rabbits in the group that was treated only with neutrons and those in the tumor control group were sacrificed humanely 30 to 70 days after tumor inoculation. The skin of the rabbits in the treatment area looked red, and they suffered slight diarrhea a few hours after BNCT treatment. The body weights of the rabbits that had undergone BNCT declined, but this weight loss was recovered within seven to ten days. Tumor-bearing rabbits were sacrificed on the 180th day following the first or second-fraction BNCT treatment. Histopathologic investigation demonstrated that no residual tumor was present in any of the livers. BA-mediated BNCT can deliver a curative dose of radiation to a tumor and the tumor vessels while sparing the normal liver tissue. Therefore, this method has the potential to be a better method for liver tumor therapy.
Key words：Boron neutron capture therapy, Boric acid, Multifocal liver tumors, Rabbit VX2 liver tumor model

摘要 II
ABSTRACT III
致謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
第1章 文獻探討 1
1.1 肝癌簡介 1
1.1.1 肝癌分類與分期 1
1.1.2 流行病學 1
1.1.3 肝癌診斷 2
1.1.4 肝癌治療 2
1.2 硼中子捕獲治療 4
1.2.1 基本原理 4
1.2.2 含硼藥物 4
1.2.3 硼中子捕獲治療於肝癌治療之研究 6
1.3 兔VX2肝腫瘤模式 8
第2章 材料與方法 10
2.1 實驗動機及目的 10
2.2 實驗架構與流程 10
2.3 硼酸溶液之配製 11
2.4 建立紐西蘭兔VX2多發病灶肝腫瘤模式 11
2.4.1 實驗動物 11
2.4.2 VX2腫瘤團塊之處理及於活體內之繼代 11
2.4.3 肝臟腫瘤團塊接種 12
2.5 硼酸水溶液於紐西蘭兔之生物體分布 12
2.5.1 血液中硼濃度及藥物動力學分析 12
2.5.2 組織硼濃度分析 13
2.6 荷多發性病灶肝腫瘤兔之硼中子捕獲治療 14
2.6.1 劑量計算 14
2.6.2 中子照射固定架及延伸匯聚管設計 14
2.6.3 荷肝腫瘤兔BNCT治療流程 15
2.7 BNCT療效評估 15
2.7.1 觀察實驗兔體重變化及飲食情況 16
2.7.2 超音波檢查 16
2.7.3 電腦斷層掃描 17
2.7.4 血液學及血清生化學檢查 17
2.7.5 組織病理切片分析 18
第3章 結果 26
3.1 多發性肝腫瘤兔模式建立 26
3.1.1 紐西蘭兔於肝腫瘤接種後之生理監控 26
3.1.2 肝腫瘤誘發之生長情形 26
3.1.3 超音波下VX2腫瘤於兔子肝臟之生長情形 26
3.2 硼酸水溶液於多發性肝腫瘤紐西蘭兔之生物體分布 27
3.2.1 硼酸於荷肝腫瘤兔之血液動力學分析 27
3.2.2 硼酸於荷肝腫瘤兔之生物體分布 28
3.3 BA-MEDIATED BNCT之療效評估 29
3.3.1 兔體基礎變化 29
3.3.2 超音波影像 31
3.3.3 電腦斷層掃描檢查 34
3.3.4血液學相關檢查 36
3.3.5 組織病理切片檢查 38
第4章 討論 77
4.1 VX2多發肝腫瘤動物模式建立 77
4.2 硼酸水溶液於紐西蘭兔之生物體分布 78
4.2.1 藥物動力學 78
4.2.2 生物體分布 79
4.3 硼中子捕獲治療之劑量計算 80
4.4 以硼酸為硼藥物進行硼中子捕獲治療肝腫瘤之療效評估 81
4.4.1 一次BNCT治療之腫瘤療效 81
4.4.2 二次BNCT治療之腫瘤療效 88
4-5 以硼酸為硼藥物進行硼中子捕獲治療之輻射損傷 91
第5章 結論 104
第6章 參考文獻 106

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