188 Re-HEDP对体外成骨细胞增殖及细胞周期的影响

目的 观察不同剂量188Re-羟基亚乙基二膦酸盐(HEDP)近距离作用对成骨细胞增殖和细胞周期的影响.方法 在体外培养的成骨细胞中加入不同放射性浓度(0,1.85,9.61,48.00,240.50,462.50,832.50和1110.00 kBq/ml)188 Re-HEDP,继续培养24 h后检测细胞的放射性计数,了解成骨细胞摄取188Re-HEDP的能力.用四甲基偶氮唑蓝(MTT)法检测成骨细胞增殖能力.测定细胞碱性磷酸酶(ALP)活性,以明确成骨细胞分化功能.采用流式细胞仪检测细胞周期变化.结果 成骨细胞摄取188Re-HEDP的能力较强,188Re-HEDP≤1110.00 kBq/ml时未观察到结合平台期.受188.Re-HEDP刺激后成骨细胞生长增殖旺盛、分化加强,成骨细胞存活率为(113.67±3.22)%-(122.00±6.58)%,ALP值为(0.42±0.02)～(0.50±0.05)U/L;188Re-HEDP≥33.30 MBq/ml时成骨细胞凋亡率增加[(6.26±0.09)%]并随剂量增大.188Re-HEDP作用后处于合成期的成骨细胞百分率明显增加,为(22.32±2.31)%-(35.58±5.18)%.结论 188Re-HEDP可能刺激成骨细胞增殖和分化,使合成期的细胞百分率增高.188Re-HEDP超过33.30 MBq/ml时引起成骨细胞凋亡,且凋亡率与其放射性浓度呈正相关.     

肿瘤骨转移疼痛患者对188Re-HEDP的耐受性研究

Objective To study the tolerance to 188Re-1-hydroxy-1 ,1-ethylidene disodium phosphonate(HEDP) in patients with bone pain caused by osseous metastases. Methods Thirty-one patients(10with prostate cancer, 9 with breast cancer, 3 with lung cancer, 5 with liver cancer, 2 with rectal cancer, 1with esophageal cancer and 1 with renal cancer) received a single injection dose of 188Re-HEDP. The patients were divided into four groups according to the injection dose: 20 MBq/kg (6 patients), 30 MBq/kg(6 patients), 40 MBq/kg (9 patients), and 50 MBq/kg (10 patients). Haematological toxicity (WHO grading) of grade Ⅲ- Ⅳ was considered unacceptable. Vital signs and adverse effects after injection were recorded for 8 weeks. Blood counts were measured weekly during a period of 8 weeks. Biochemical parameters and electrocardiogram were assayed at week 4 and 8. Statistical analysis was performed for per-protocol (pp) population (t-test). Results Twenty-seven patients belonged to PP population with 5 in the group of 20 MBq/kg, 5 in the group of 30 MBq/kg, 8 in the group of 40 MBq/kg and 9 in the group of 50 MBq/kg.No obvious adverse effects and no significant change of vital signs, electrocardiogram, liver and renal function were found after injection. Alkaline phosphatase was slightly higher than baseline at week 4 and 8 after therapy, but the difference was not statistically significant. In the 20 MBq/kg group, reversible grade Ⅰ leucopenia was noted in 1 patient. In the 30 MBq/kg group, 2 patients showed reversible grade Ⅰ leucopenia including 1 alone with reversible grade Ⅲ thrombopenia. In the 40 MBq/kg group, reversible grade Ⅰ leucopenia and thrombopenia was observed in 1 patient and reversible grade Ⅱ leucopenia and thrombopenia in another patient. In the .50 MBq/kg group, 3 patients showed reversible grade Ⅱ leucopenia. The lowest level of thrombopenia was at week 4(143.5 × 109/L), leucopenia at week 6 (5.4 × 109/L) and anaemia at week 8(t = 3.1325, 3.3156, 3.4917, all P ＜ 0. 05 compared with baseline). At week 8, the mean level of platelet and leucocyte recovered to baseline. "Bounce pain" was found in 2 of 27 patients (7.41%).Conclusions The dose of 20 MBq/kg, 30 MBq/kg, 40 MBq/kg or 50 MBq/kg of 188Re-HEDP do not cause significant side effects on cancer patients with bone metastases, though there is a tendency that the haematological toxicity may increase as the dose of 188Re-HEDP increases.     

188Re—HEDP治疗肿瘤骨转移痛药代动力学研究

目的研究188Re标记的1-羟基-1,1-二膦酸钠乙烷（即依替膦酸盐,HEDP）在肿瘤骨转移患者体内的分布和排泄,分析不同剂量188Re—HEDP在患者体内的药代动力学特点。方法将40例肿瘤骨转移患者分为4组,每组10例,4组分别按体质量“弹丸”式经肘静脉注射188Re—HEDP20,30,40和50MBq／kg,给药时及给药后1,2,4,5,12,24,36,48,60和72h分别用SPECT仪采集胸前区和前后位、后前位全身图像,并收集患者尿液,测量放射性。利用感兴趣区（ROI）技术在左心室区测得经本底校正的放射性,作为血液放射性。将1h全身前位、后位放射性总计数率经死时间和时间衰减校正后的几何平均值设定为100％注射剂量（ID）,据此估算上述各时间点全身和各器官的百分注射剂量率（％ID）。各组间的计量资料采用元、中位数、范围等表示,组间比较采用方差分析或t检验。结果20～50MBq／kg范围内,188Re—HEDP在体内的时间-放射性曲线下面积（AUC）与其剂量呈线性关系,r^2=0．9376。4组均符合静脉给药二室模型,AUC值中位数分别为3．32×10^5,3．97×10^5,7．83×10^5,8．58×10^5;分布速度常数（α值）中位数分别为0．06,0．05,0．04,0．06;消除速度常数（B值）中位数分别为1．16×10^-3,1．16×10^-3,1．03×10^-3,1．15×10^-3;指数项系数A值中位数分别为3591．21,4858．23,5642．48,4167．05;指数项系数B值中位数分别为293．97,352．95,614．41,1063．82;药物分布相半衰期T1/2值中位数分别为12．51,12．83,15．41,12．02min;药物消除相半衰期T1／2（β）中位数分别为595．47,596．50,673．09,600．93min。骨组织是摄取188Re—HEDP的主要组织,给药后4h放射性摄取高,约为40％ID,其他组织未见明显摄取188Re—HEDP0188Re．HEDP主要通过泌尿系统排泄,给药后24h排出66．79％ID,其中74％在给药后5h内排出。结论20～50MBq／kg范围内,188Re—HEDP在机体内的药代动力学符合血管给药二室模型。188Re—HEDP T1/2（β）平均为616．50min。188Re—HEDP主要通过泌尿系统排泄;骨组织是摄取188Re—HEDP的主要组织。     

紫杉胶囊急性毒性和反复给药毒性实验研究

目的观察紫杉胶囊的急性毒性和反复给药毒性,指导临床安全合理用药。方法急性毒性采用最大给药剂量法（10g/kg）,观察给药后小鼠出现毒性反应。反复给药毒性实验分为0.25、0.5、1.0g/kg3个给药组（分别相当于临床人用量的8、17、33倍）及溶剂对照组,连续给药90天。停药后恢复期观察4周。检测指标包括动物一般状况、血液学和凝血、血清生化、尿检查及病理组织学等内容。结果急性毒性实验给药后部分动物观察到了眼睑下垂,活动减少,第2天、第4天各有1只小鼠死亡。紫杉胶囊0.5、1.0g/kg连续给药90天。可见雌性大鼠进食量一过性降低,体重下降;AST和ALT增高,给药结束时组织病理学检查可见0.5、1.0g/kg组肝脏片状坏死;骨髓血涂片结果显示骨髓造血细胞轻度抑制,恢复期结束时均未见异常。结论ICR小鼠单次灌胃紫杉胶囊的LD50大于10g/kg。SD大鼠灌胃紫杉胶囊90天反复给药毒性试验,其无毒反应剂量为0.25g/kg。0.5、1.0g/kg动物毒性反应主要为可逆性的肝脏毒性和骨髓轻微抑制作用。上述研究结果为紫杉胶囊的临床安全合理应用提供了参考。     

髓母细胞瘤患者全脑全脊髓放疗的血液学毒性观察

目的了解全脑全脊髓放疗对髓母细胞瘤患者血象的影响,分析其危险因素。方法回顾性地分析30例髓母细胞瘤患者在接受全脑全脊髓放疗期间血象变化,按照下降程度分为正常与轻度抑制（0/Ⅰ/Ⅱ）和重度抑制（Ⅲ/Ⅳ）,分析性别、年龄、放疗累积剂量与血液学毒性的相关性。结果 96.7%（29/30）的患者出现白细胞减少,63.3%（19/30）的患者出现血小板减少,70%的患者在放疗开始2周内出现白细胞减少,放疗的累积剂量与血液学毒性有关（P〈0.001）。结论大部分患者在前两周出现白细胞减少,放疗累积剂量（Dt）0～18 Gy出现血液学毒性的患者中发生重度抑制的白细胞血液学毒性的比例更高,放疗开始2周内出现白细胞减少比例高,应密切观察血象变化,发生血液学毒性时应及时处理。     

前药dl-PHPB在Beagle犬中反复给药毒性及伴随毒代动力学研究

目的评价I类抗脑缺血新药2-（α-羟基戊基）苯甲酸钾（dl-PHPB）在Beagle犬中反复给药30d的毒性及伴随毒代动力学。方法 Beagle犬反复给药30d,给药剂量分别为6、18、54mg/kg（分别相当于临床人体用量的3.6、10.8和32.4倍）并设溶剂对照组,停药后恢复期观察3周。同时采用HPLC-UV方法测定不同剂量下首次和末次给药的血清药物浓度。结果 54mg/kg剂量组的主要毒性反应为部分动物给药过程中出现头部颤抖,给药结束时可见血尿素氮（BUN）、肌酐（Cr）和尿pH值有所增加,相关脏器病理组织学检查未见异常;恢复期结束时上述指标均恢复正常。在6、18、54mg/kg剂量下,药后1h内dl-PHPB即完全转化为丁基苯酞（dl-NBP）。首次给药后,其活性代谢物dl-NBP的AUC0-∞分别为2.8、7.2、32.5μg·h^-1·ml^-1,末次给药dl-NBP的AUC0-∞分别为2.9、8.1、38.7μg·h^-1·ml^-1。其转化为dl-NBP的暴露比（AUC30th/AUC1st）分别为1.02、1.12和1.17。结论 Beagle犬静脉滴注dl-PHPB30d连续给药非毒性反应剂量为18mg/kg。伴随毒代动力学研究显示dl-PHPB的毒性反应与其快速转化为dl-NBP密切相关。     

188Re-IGF-1类似物对胰腺癌细胞Patu8988的增殖抑制与诱导凋亡实验

目的 研究188 Re-IGF-1类似物(IGF-1A)对胰腺癌Patu8988细胞的增殖抑制效应和诱导凋亡作用.方法 (1)制备188 Re-IGF-1A,用四甲基偶氮唑蓝(MTT)实验检测给药后细胞增殖情况,细胞按给药情况分为对照组、IGF-1A组(1、5、10、20 μg)、188ReO4-组(0.37、1.85、3.70、7.40 MBq)和188 Re-IGF-1A组(0.37、0.74、1.85 MBq).188ReO4-组和188Re-IGF-1A组分别在给药后1～7d,IGF-1A组分别在给药后1 ～6d,每天用MTT比色法测定其吸光度(A)值,计算细胞生存率和抑制率.(2)将1×106个细胞接种于培养瓶中,分188 ReO4-组和188 Re-IGF-1A组(均设1.85、3.70、7.40 MBq 3个剂量),在给药后3d用流式细胞仪检测细胞凋亡率.(3)36只荷人胰腺癌裸鼠,瘤内注射188Re-IGF-12.28-4.81 MBq,分别在15 min,1、4h,1、3和5d显像后处死裸鼠6只,计算各组织的％ID/g和每MBq活度的吸收剂量(mGy/MBq).对数据行单因素方差分析.结果 (1) IGF-1A和188Re-IGF-1A能抑制Patu8988细胞生长.加入188Re-IGF-1A后4d,1.85 MBq亚组抑制率达到(90.75±5.20)％,高于相同化学剂量的IGF-1A(5 μg)组或相同放射性活度的188ReO4-组[(49.50±2.39)％与(23.00±4.21)％],差异有统计学意义(F =554.724,P＜0.01).(2)给药1.85、3.70、7.40 MBq3 d后,188Re-IGF-1A组漂浮细胞比例分别为(16.56±0.95)％、(33.39±5.93)％和(43.76±1.38)％,漂浮细胞的凋亡率分别为(12.70±2.27)％、(17.80±1.51)％和(23.23±1.22)％.(3)荷瘤鼠瘤内注射188Re-IGF-1A后15 min和1、3、5d肿瘤内放射性摄取分别为(39.30±17.98)、(10.59±9.39)、(5.32±1.53)和(5.30±2.28) ％ID/g.肿瘤内吸收剂量为5165.8 mGy/MBq.结论 188Re-IGF-1A对胰腺癌细胞生长有明显的抑制作用,并可诱导细胞凋亡;瘤内注射后肿瘤部位摄取较高.     

左乙拉西坦与托吡酯对儿童癫痫的疗效比较

目的：研究比较左乙拉西坦（LEV）和托吡酯（TPM）对儿童癫痫单药治疗的疗效及安全性。方法：纳入2007-01～2009-06收治的儿童癫痫患者45例,随机分组为左乙拉西坦治疗组（A组）20例,托吡酯治疗组（B组）25例。治疗剂量：A组初始剂量25mg/d,每周增加25mg,目标量为6～8mg/（d.kg）,在6～7周内达到目标剂量。B组起始剂量为0.5～1.0mg/（d.kg）,根据病情每周增加0.5～1.0mg/（d.kg）,最终维持剂量为4～6mg/（d.kg）。随访3～12个月。结果：A组左乙拉西坦单药治疗的总有效率为85%,B组托吡酯单药治疗的总有效率为88%。结论：左乙拉西坦和托吡酯对于儿童癫痫的单药治疗是安全有效的。     

清火排毒化肿胶囊急性毒性及长期毒性研究

目的 :探讨清火排毒化肿胶囊单次或多次给药后 ,动物出现的毒性反应及其性质和程度 ,寻找药物的安全范围 ,为临床用药提供科学依据。方法 :急性毒性试验为测定小鼠最大给药量方法。长期毒性试验为大鼠连续以清火排毒化肿胶囊 2 7g/kg、1 35 g/kg或 0 4 5 g/kg·体重 ,灌胃给药 12周 ,观察大鼠各项生理、病理指标变化 ,停药后继续观察 2周。结果 :清火排毒化肿胶囊对小鼠一日内灌胃的最大药量为 10 8g/kg·体重。长期毒性试验结果显示 ,1 35 g/kg组和2 7g/kg组与对照组比较 ,WBC分类和CR有统计学意义 (P <0 0 5或P <0 0 1) ;给药组与对照组比较 ,心、肺脏器权重系数差别有统计学意义 (P <0 0 5或P <0 0 1) ;病理组织学检查 ,高剂量组和对照组比较无统计学意义。恢复期末 ,给药组与对照组比较 ,各项观察指标均无统计学意义 (P >0 0 5 )。结论 :清火排毒化肿胶囊按拟定临床剂量及疗程服用是安全的。     

G-CSF联合SB203580对4Gy照射小鼠免疫系统的作用

目的 研究G-CSF联合p38抑制剂SB203580 （SB）对免疫细胞辐射损伤的作用.方法 C57BL/6雄性小鼠按体质量随机分为对照组、照射组和给药组.照射组和给药组给予4 Gy全身照射.给药组小鼠给予腹腔注射G-CSF和SB,G-CSF于4Gy照射后2h和6h给药（1μg/只）,每天2次,连续给药5d,SB于照射后24h给药（15 mg/kg）,隔日给药,共给药5次.照射后10d测外周血计数,进行白细胞CD4、CD8、B220检测、胸腺细胞CD4、CD8检测和骨髓细胞活性氧检测.结果 照射组外周血计数和CD8、B220比例下降,而胸腺细胞中CD4＋CD8＋细胞比例及骨髓细胞活性氧水平显著增加.与照射组相比,联合给药组外周血红细胞数、血小板、CD4、CD8细胞比例升高,胸腺细胞中CD4＋CD8＋细胞比例下降.结论 G-CSF联合SB对4 Gy照射引起的免疫细胞损伤存在保护作用.     

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200x10(9)/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200x10(9)/l. In patients with thrombocyte counts significantly above 200x10(9)/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%-75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.     

Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added ¹⁸⁸Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq ¹⁸⁸Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count <200×10⁹/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of ¹⁸⁸Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200×10⁹/l. In patients with thrombocyte counts significantly above 200×10⁹/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%–75% of patients receiving a dose of 2.6 GBq or more of ¹⁸⁸Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of ¹⁸⁸Re-HEDP. Received 7 July and in revised form 6 October 1999     

Dosimetry of 188Re-hydroxyethylidene diphosphonate in human prostate cancer skeletal metastases.

188Re-Hydroxyethylidene diphosphonate ((188)Re-HEDP) was used in previous studies for the palliative treatment of metastatic bone pain. However, the kinetic and radiation-absorbed doses have not been well documented. Therefore, the aim of this study was to gather dosimetric data for (188)Re-HEDP. METHODS: Thirteen prostate cancer patients with skeletal involvement were treated with 2,700-3,459 MBq (mean dose, 3,120 MBq) (188)Re-HEDP. Patients underwent whole-body scans 3, 20, and 28 h after therapy. The effective half-life, residence time, and radiation-absorbed dose values were calculated for the whole body, bone marrow, kidneys, and bladder as well as for 29 bone metastases. The urinary excretion rate was determined in 6 urine samples of each patient collected over 48 h at 8-h intervals beginning immediately after the administration of (188)Re-HEDP. After injection of (188)Re-HEDP, blood samples were taken weekly for 6 wk, and platelet and leukocyte counts were performed. RESULTS: The mean effective half-life was 15.9 +/- 3.5 h in bone metastases, 10.9 +/- 2.1 h in the bone marrow, 11.6 +/- 2.1 h in the whole body, 12.7 +/- 2.2 h in the kidneys, and 7.7 +/- 3.4 h in the bladder. The following radiation-absorbed doses were calculated: 3.83 +/- 2.01 mGy/MBq for bone metastases, 0.61 +/- 0.21 mGy/MBq for the bone marrow, 0.07 +/- 0.02 mGy/MBq for the whole body, 0.71 +/- 0.22 mGy/MBq for the kidneys, and 0.99 +/- 0.18 mGy/MBq for the bladder. (188)Re-HEDP showed a rapid urinary excretion within the first 8 h after therapy, with 41% of the (188)Re-HEDP administered being excreted. Forty-eight hours after therapy, the excretion rate was 60% +/- 12%. Only 1 patient showed a decrease of platelet count below 100 x 10(9) counts/L. None of the patients presented with a decrease of leukocyte count below 3.0 x 10(9) counts/L. CONCLUSION: (188)Re-HEDP is an effective radiopharmaceutical used in the palliative treatment of metastatic bone pain. The radiation-absorbed dose is acceptable for bone pain palliation with low doses for the normal bone marrow and the whole body.     

<Superscript>188</Superscript>Re-HEDP combined with capecitabine in hormone-refractory prostate cancer patients with bone metastases: a phase I safety and toxicity study

Purpose

¹⁸⁸Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of ¹⁸⁸Re-HEDP and capecitabine (Xeloda®) was tested in a clinical phase I study.

Methods

Patients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m² per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg ¹⁸⁸Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with ¹⁸⁸Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of ¹⁸⁸Re-HEDP.

Results

Three patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m² per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of ¹⁸⁸Re-HEDP.

Conclusion

Capecitabine may be safely used in combination with ¹⁸⁸Re-HEDP in a dose of 2,500 mg/m² per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.

     

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (¹⁸⁶Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using ¹⁸⁶Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the ¹⁸⁶Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq ¹⁸⁶Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 10⁹/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of ¹⁸⁶Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of ¹⁸⁶Re-HEDP has been initiated.     

A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

Evaluation of toxicity and efficacy of 186Re-hydroxyethylidene diphosphonate in patients with painful bone metastases of prostate or breast cancer.

Twenty-eight patients (12 men with prostate cancer, 16 women with breast cancer) were included in a phase II trial to evaluate the efficacy of 186Re-hydroxyethylidene diphosphonate (HEDP) on pain from bone metastasis and the toxicity of this agent. METHODS: After intravenous administration of 1295 MBq 186Re-HEDP, the efficacy was evaluated by means of a daily log. RESULTS: We observed an objective response in 67% of prostate cancer patients and in 36% of breast cancer patients. The mean duration of response was 45 d for prostate cancer patients and 24 d for breast cancer patients. No major adverse effects were observed. Marrow toxicity did not exceed grade 2 for white blood cells and grade 3 for platelets using National Cancer Institute criteria. CONCLUSION: 186Re-HEDP provides safe symptomatic relief of pain in prostate cancer patients. The benefit of this treatment is less clear in breast cancer patients. Further studies should be conducted to evaluate treatment by 186Re-HEDP at an earlier stage of the disease.     

125I粒子不同分布组织间植入对荷人胃癌裸鼠移植瘤疗效的影响

目的 探讨125I粒子总活度相同时,不同分布的组织间植入对荷人胃癌裸鼠移植瘤疗效的影响.方法 建立人胃低分化腺癌BGC-823细胞裸鼠皮下移植瘤模型32只,按随机数字表法分为实验组和对照组.实验组植入总活度33.30 MBq125I粒子,按照植入单枚活度及分布不同分为高活度组(33.30 MBq×1枚)、中活度组(16.65 MBq×2枚)、低活度组(11.10 MBq×3枚);对照组植入空源粒子.每组8只裸鼠模型.比较实验和对照组及125I粒子不同分布状态下对移植瘤体积的抑制率、组织病理学改变、局部皮肤反应、裸鼠体质量和存活率.采用方差分析和秩和检验对数据进行统计学处理.结果 各组存活率均为100%.125I粒子植入第30天裸鼠体质量各组比较,差异无统计学意义[高、中、低活度及对照组分别为(26.44±1.07)、(26.58±0.51)、(27.15±1.37)和(26.92±0.60)g,F=2.23,P>0.05].第30天各实验组125I粒子对肿瘤体积抑制率分别为92.47%,97.15%和89.01%;平均体积各实验组[高、中、低活度组分别为(138.85±16.45)、(52.52±30.54)、(202.72±126.97)mm3]与对照组[(1843.99±447.63)mm3]比较,差异均有统计学意义(t值分别为3.092,3.376,3.269,P均<0.05),中活度组和低活度组组间比较差异有统计学意义(t=2.308,P<0.05),高活度组分别和中活度组、低活度组组间比较差异均无统计学意义(t值分别为1.300,1.007,P均>0.05).高活度组与中活度组组织病理学分级按直肠癌消退分级标准(RCRG)均为RCRG 1级;低活度组3只为RCRG 3级,4只为RCRG 2级,1只为RCRG 1级.中、低活度组均未出现放射性损伤,高活度组中4只裸鼠于125I粒子植入后9～12 d出现放射治疗肿瘤学组织(RTOG)1～2级放射性损伤.结论 125I粒子植入治疗中单源活度的选择和分布方式可直接影响疗效和放射性损伤的程度.