153Sm-Annexin V凋亡显像的实验研究

  目的   探讨放射性核素153Sm标记Annexin V凋亡显像的可行性。   方法  采用环二乙三胺五醋酸(DTPA) 法进行153Sm-Annexin V制备, 并进行物理、化学及生物学检测。应用153Sm-Annexin V进行体外细胞培养及荷瘤小鼠动物凋亡显像实验。   结果  经环DTPA法制备的153Sm-Annexin V无色透明, pH为7.4, 比活度100μg/10 mCi/2 mL; 放化纯RCP > 90%, 标记率为88.6%;无菌, 无热原, LD₅₀ > 333μg/kg体质量, 血浆半衰期13 min; 体外细胞培养及荷瘤小鼠动物凋亡显像实验均阳性。   结论  153Sm-Annex in V作为放射性核素凋亡显像剂, 标记率高, 半衰期相对较长, 利于进行连续追踪监测、捕捉细胞凋亡活动的高峰期, 进而确立最佳凋亡显像时间窗, 有广泛的临床应用前景。      

18F-SFB-Annexin B1探测化疗后肿瘤细胞凋亡的实验研究

背景与目的：诱导细胞凋亡是肿瘤化疗的机制之一,分子影像能在活体内无创、动态地检测细胞凋亡,有助于药物筛选和疗效分析。本研究旨在探讨N-琥珀酰亚胺-4-氟苯甲酸酯偶联的氟-18-膜联蛋白B1(¹⁸F-SFB-AnnexinB1)显像剂早期评价化疗诱导细胞凋亡的可行性。方法：以SFB作为中间体将¹⁸F标记到AnnexinB1上。了解¹⁸F-SFB-Annexin B1在健康小鼠体内的生物分布特性。建立Walker-256荷瘤小鼠模型,随机分为两组,化疗组腹腔注射环磷酰胺(CTX 200 mg/kg,n=3),对照组注射等体积无菌0.9%的氯化钠溶液(n=3)。24 h后静脉注射1⁸F-SFB-Annexin B1,分别于注射后1、2、3、4 h进行PET/CT显像。比较肿瘤/肌肉放射性摄取率比值(T/M)与原位缺口末端标记(TUNEL)染色法测定凋亡指数(AI)的关系。结果：18F-SFBAnnexinB1放化纯度>95%,生物分布显示肾脏放射性最高,其次为肝、脾和心肌,显像剂在体内清除速率快。化疗组与对照组各时间点T/M比值分别为4.38±0.56、6.75±1.16、6.44±1.12、4.81±0.17和2.35±0.14、2.99±0.55、3.04±0.41、2.33±0.47,差异有统计学意义(F分别为23.790、16.913、14.046、77.517,P均<0.05)。TUNEL染色AI分别为(21.00±0.04)%和(8.58±0.01)%,差异有统计学意义(F=21.539,P<0.05),且T/M值与AI间有很好的相关性(r=0.91,P<0.05)。结论：¹⁸F-SFB-AnnexinB1能早期反映化疗诱导的细胞凋亡,有望用于活体细胞凋亡分子显像和早期疗效判断。     

核素肾动态显像对非小细胞肺癌化疗后早期肾损害的评价

目的探讨核素肾动态显像对非小细胞肺癌化疗早期肾损伤的评价。方法对22例非小细胞肺癌（NSCLC）患者首次化疗2个周期前后行99mTc—DTPA核素肾动态显像,测定肾小球滤过率（GFR）、高峰时间（Th）、半排时间（C1/2）;同时检测血清肌酐（Scr）、尿素氮（BUN）。结果22例患者血清GFR水平化疗后较化疗前明显下降（P〈0．05）;双肾血流灌注峰值下降,肾排泄速率减慢,表现为Tb、C1/2延长（P〈0．05）。22例患者血清Scr水平化疗前后无统计学差异（P〉0．05）;而BUN水平两组之间差异显著（P〈0．01）。结论核素肾动态显像,较常规肾功能检查更能全面、定量地监测NSCLC化疗后’肾功能早期损伤。     

99Tcm-Annexin B1探测荷瘤鼠化疗后肿瘤细胞凋亡的实验观察

目的:探讨~(99)Tc~m-Annexin B1探测化疗后肿瘤细胞凋亡的潜力与可行性。方法:乳腺癌细胞MDA-MB-435荷瘤小鼠经大剂量(30mg/kg)紫杉醇单次化疗后,注射~(99)Tc~m-Annexin B1,计算化疗后不同时间(0、5、10、15、20和25h)每克肿瘤组织摄取~(99)Tc~m-Annexin B1的百分注射剂量率(%ID/g)。肉瘤细胞W256荷瘤大鼠经大剂量(200mg/kg)环磷酰胺单次化疗后24h注射~(99)Tc~m-Annexin B1,对照组荷瘤大鼠注射生理盐水;行SPECT平面显像观察肿瘤摄取情况。结果:乳腺癌荷瘤小鼠化疗后15h,肿瘤摄取~(99)Tc~m-Annexin B1达高峰,由0h的(0.15±0.013)%ID/g上升至(0.22±0.026)%ID/g。肿瘤对~(99)Tc~m-Annexin B1的摄取与肿瘤细胞凋亡指数(AI)具有相关性,r=0.88,P<0.01。W256细胞荷瘤大鼠化疗后24h显像发现,肿瘤对~(99)Tc~m-Annexin B1的摄取较对照荷瘤大鼠显著升高,对照组的肿瘤与非肿瘤摄取比值(T/B)为1.39±0.21,化疗组为2.57±0.43。结论:~(99)Tc~m-Annexin B1对探测化疗后肿瘤细胞凋亡具有潜力与可行性。     

化疗前后卵巢癌细胞及外周血淋巴细胞凋亡及凋亡因子的流式细胞检测及临床意义

目的　探讨化疗前后卵巢癌细胞及外周血淋巴细胞凋亡率及凋亡因子Ｆａｓ和Ａｐｏ ２．７含量及其临床意义。方法　从６８ 例化疗前后的卵巢癌患者腹水中提取富含癌细胞的悬液,用Ａｎｎｅｘｉｎ Ｖ／ＰＩ双染法分辨凋亡细胞,并用２种凋亡因子单克隆抗体标记上述细胞,均用流式细胞仪检测。结果　化疗后卵巢癌细胞凋亡率显著高于化疗前（Ｐ＜ ０．０１）,被Ｆａｓ及Ａｐｏ ２．７标记癌细胞率也显著性增加（Ｐ＜ ０．０５）;化疗使外周血淋巴细胞凋亡率及凋亡因子有不同程度的增加;结论　通过对化疗前后卵巢癌细胞凋亡的检测有助于判断化疗效果,有重要的临床意义。     

^99Tc^m-Annexin B1探测荷瘤鼠化疗后肿瘤细胞凋亡的实验观察

目的：探讨^99Tc^m-Annexin B1探测化疗后肿瘤细胞凋亡的潜力与可行性。方法：乳腺癌细胞MDA-MB-435荷瘤小鼠经大剂量（30mg／kg）紫杉醇单次化疗后，注射^99Tc^m-Annexin B1，计算化疗后不同时间（0、5、10、15、20和25h）每克肿瘤组织摄取^99Tc^m-Annexin B1的百分注射剂量率（％ID／g）。肉瘤细胞W256荷瘤大鼠经大剂量（200mg／kg）环磷酰胺单次化疗后24h注射^99Tc^m-Annexin B1，对照组荷瘤大鼠注射生理盐水；行SPECT平面显像观察肿瘤摄取情况。结果：乳腺癌荷瘤小鼠化疗后15h，肿瘤摄取^99Tc^m-Annexin B1达高峰，由0h的（0．15±0．013）％ID／g上升至（0．22±0．026）％ID／g。肿瘤对^99Tc^m-Annexin B1的摄取与肿瘤细胞凋亡指数（AI）具有相关性，r=0．88，P〈0．01。W256细胞荷瘤大鼠化疗后24h显像发现，肿瘤对^99Tc^m-Annexin B1的摄取较对照荷瘤大鼠显著升高，对照组的肿瘤与非肿瘤摄取比值（T／B）为1．39±0．21，化疗组为2．57±0．43。结论：^99Tc^m-Annexin B1对探测化疗后肿瘤细胞凋亡具有潜力与可行性。     

化疗前后卵巢癌细胞及外周血淋巴细胞凋亡及凋亡因子的流？…

目的 探讨化疗前后卵巢癌细胞及外周血淋巴细胞凋亡率及凋亡因子Ｆａｓ和Ａｐｏ２．７含量及其临床意义。方法 从６８例化疗前后的卵巢癌患者腹水中提取富含癌细胞的悬ｎｎｅｘ－ｉｎＶ／ＰＩ双染法分辨凋亡细胞,并用２种凋亡因子单克隆抗体标记上述细胞,均用流式细胞仪检测,结果 化疗后卵巢癌细胞凋亡率显著高于化疗前（Ｐ〈０．０１）,被Ｆａｓ及Ａｐｏ２．７标记癌细胞率也显著性增加（Ｐ〈０．０５）,化疗使外周血淋巴细     

~(99m)Tc-MIBI显像对乳腺肿块良恶性的鉴别及病理学分析

目的 探索此项检查诊断乳腺癌的临床应用价值及其与病理类型的关系.方法 60例女性乳腺肿块病人,静脉注射~(99m)TC-MIBI740～925MBq/入后5～10min静态显像.计算T/NT比值,检查后一周内手术.结果此方法诊断乳腺癌的灵敏度为80.4%,特异性为92.8%.其阳性率随组织病理学特点不同而差异明显.对癌细胞密度相对较低的乳腺癌显像时易造成假阴性.结论 ~(99m)TC-MIBI乳腺显像对鉴别乳腺良恶性病变,尤其在评价内乳淋巴结和腋窝淋巴结是否转移及术后残留复发方面具有良好的临床应用价值.     

钙拮抗剂增加化疗中卵巢癌细胞凋亡相关因子的研究

目的 探讨钙拮抗剂（ＣＡ）对促进化疗化物诱发卵巢癌细胞凋亡的作用。方法：从６８例首次手术及１７例复发卵巢癌患者腹水中提取富含癌细胞的悬液,应用３种荧光单克隆抗体Ｐ１７０,ＣＤ９５,及Ａｐｏ,２．７标记,经流式细胞仪检测,结果 应用ＣＡ组化疗后癌细胞ＣＤ９５及Ａｐｏ２．７含量均高于姐（Ｐ〈０．０５）,对癌细胞Ｐ１７０含量无明显影响（Ｐ〉０．０５）,复发组癌细胞Ｐ１７０含量显著高于初发手术组（Ｐ〈０．     

异博定增加化疗中卵巢癌细胞凋亡的研究

目的　探讨异博定对促进化疗药物诱使卵巢癌细胞增加凋亡因子表达的作用。方法　从 48例首次手术及 17例复发卵巢癌患者腹水中提取富含癌细胞的悬液 ,应用三种荧光单克隆抗体P170、CD95及Apo2 .7标记 ,经流式细胞仪检测。结果　应用异博定化疗后癌细胞CD95及Apo2 .7表达含量均高于对照组 ;异博定对癌细胞P170表达含量无明显影响 ;复发组癌细胞P170表达含量显著高于初发手术组 ;化疗可使外周血淋巴细胞CD95及Apo2 .7表达含量增加。结论　本研究提示异博定具有加强化疗药物增加卵巢癌细胞凋亡的作用 ,特别是对耐药性患者具有重要的临床应用价值。     

Thallium-201核素显像在骨肉瘤新辅助化疗疗效评估中的价值

目的 探讨Thallium-201(TI-201)核素显像对骨肉瘤术前新辅助化疗疗效评估的意义.方法 34例骨肉瘤患者在术前新辅助化疗前、后进行TI-201核素显像,对所采集的图像数据进行定性和半定量分析,通过测量肿瘤病灶与正常组织的放射性计数,计算摄取比(UR)和变化率(AR);同时测量肿瘤面积(S),计算面积比(SR).对患者术后肿瘤病理标本进行分析,根据肿瘤坏死率(TNR)将其分为3级,Ⅰ级:TNR＜50%;Ⅱ级:TNR为50%～90%;Ⅲ级:TNR＞90%.将AR、SR与TNR进行直线相关性分析.结果 TNR Ⅰ级(6例)、Ⅱ级(18例)和Ⅲ级(10例)患者的早期相和延迟相AR分别为3.19%±8.40%和-26.29%±63.61%、40.07%±11.95%和39.30%±9.87%、78.32%±8.33%和63.26%±6.06%,AR与TNR之间存在良好相关性(r=0.71).新辅助化疗后,肿瘤面积缩小18例(52.9%),肿瘤面积变化不明显8例(23.5%),肿瘤面积增大6例(17.6%),肿瘤sR与TNR之间无相关性.结论 新辅助化疗后,AR与TNR存在良好的相关性,对骨肉瘤化疗疗效的评估有重要意义.     

Dynamic magnetic resonance imaging assessment of vascular targeting agent effects in rat intracerebral tumor models

We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting α(V)-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65 ± 10%, whereas bevacizumab reduced tumor rCBV by 31 ± 10% at 7 days (P < .001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P = .0004 for group, P = .0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting α(V)-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy.     

Apoptosis- and necrosis-inducing potential of cladribine, cytarabine, cisplatin, and 5-fluorouracil in vitro: a quantitative pharmacodynamic model

Purpose: The purpose of this study was to characterize the concentration-dependent induction of apoptosis by anticancer drugs in vitro. Methods: The apoptosis- and necrosis-inducing potential of the anticancer drugs cladribine (CDA), cytarabine (ARA-C), cisplatin (CDDP), and 5-fluorouracil (5FU) were studied in vitro in the human leukemia cell lines HSB2 and Jurkat using a flow-cytometry assay that permits the simultaneous quantification of vital, apoptotic, and necrotic cells by double-staining with fluorescein isothiocyanate (FITC)-labeled Annexin-V and propidium iodide. The results were fit to different multicompartmental models and the sensitivity of the cell lines to apoptosis and necrosis was estimated. Results: A time- and dose-dependent decrease in vital cells as well as an increase in apoptotic and necrotic cells was observed in HSB2 cells upon continuous incubation with 10⁻⁵–10⁻⁷ M CDA, 10⁻⁵–10⁻⁸ M ARA-C, 5 × 10⁻⁵–5 × 10⁻⁶ M CDDP, and 10⁻⁴–10⁻⁵ M 5FU, whereas no effect was observed relative to controls upon incubation with 10⁻⁸–10⁻⁹ M CDA, 10⁻⁹ M ARA-C, 10⁻⁷–10⁻⁸ M CDDP, or 10⁻⁶–10⁻⁹ M 5FU. In Jurkat cells, apoptosis- and necrosis-inducing effects were observed at 10⁻⁴–5 × 10⁻⁶ M CDA, 10⁻⁵–10⁻⁷ M ARA-C, 5 × 10⁻⁵–5 × 10⁻⁶ M CDDP, and 10⁻⁴–10⁻⁵ M 5FU. In all experiments, apoptotic cells reached a peak after 6–48 h of drug exposure. These data were best fit by a model in which vital cells became irreversibly apoptotic by a direct pathway and necrotic by an irreversible indirect pathway following the apoptotic state (mean R=0.9876; range 0.9510–0.9993; mean modified Akaike's information criterion 3.88; range 1.86–5.82) and the rate constants of either pathway (Kva and Kan, respectively) were assessed. The sensitivity of both cell lines to apoptosis and necrosis (expressed as EC₅₀ and E_max values) induced by the anticancer drugs could be calculated from the sigmoidal concentration-effect curves. Furthermore, it was shown that drug treatment (10⁻⁶ M CDA or 10⁻⁶ M ARA-C) potentiated the apoptosis-inducing effects of irradiation (6 Gy) but not its necrosis-inducing potential. Conclusion: This study demonstrates that CDA, ARA-C, CDDP, and 5FU possess concentration-dependent apoptosis-inducing potential in the cell lines studied. The cytotoxic mechanism and cell-killing potential of these drugs is different, which is reflected by different EC₅₀ and E_max values. Furthermore, a method for pharmacodynamic modeling is introduced that permits a quantitative approach for the assessment of the sensitivity of tumor cells to anticancer drugs and combined treatments. Received: 13 July 1997 / Accepted: 5 November 1997     

123 I-血管内皮生长因子结合位点在人类肿瘤细胞的表现特征

目的 探索肿瘤血管内皮生长因子（VEGF）受体（VEGFR）在人类肿瘤细胞的表现特征.方法 将123 I-VEGF165和123 I-VEGF121标记于人脐静脉内皮细胞（HUVEC）、人类肿瘤细胞株（HMC-1、A431、KU812、U937、HEP-1、HEP-G2、HEP-3B、Raji）、多种人体肿瘤及邻近的非瘤组织和外周血液细胞.统计特异性结合位点最大结合容量（Bmax）值、解离常数（Kd）以及放射性同位素的50％特异性结合所需浓度（IC50）数值.判断各种细胞与123I-VEGF165和123I-VEGF121结合亲和力、数量、特异性.结果 在HUVEC表面发现两种123I-VEGF165结合位点,而123I-VEGF121是单类结合位点.123I-VEGF121位于特定细胞株（HUVEC、HEP-1、HMC-1）和特殊的早期肿瘤（早期黑色素瘤、乳腺导管内癌、卵巢癌和脑膜瘤）中.与外周血液细胞和非瘤组织相比,肿瘤细胞的VEGFR数量明显较多.在123I-VEGF165标记的VEGFR中,早期黑色素瘤、乳腺导管内癌、肝细胞癌、乳头状甲状腺癌、卵巢癌、肾细胞癌的Bmax值分别为45±13、13±3、25 ±8、5±2、42±12、20 ±6.而在123I-VEGF121标志的VEGFR中,早期黑色素瘤、乳腺导管内癌、卵巢癌的Bmax值分别为30 ±8、8±3、20 ±6.123I-VEGF165和123I-VEGF121与诸多人体肿瘤细胞或组织具有特异性结合能力.与123I-VEGF121相比,123I-VEGF165可与更多不同种类的肿瘤细胞相结合,且容量大.结论 123I-VEGF165可能是肿瘤体内成像的一个潜在有效靶点,有望用于肿瘤的诊断与治疗.     

131I-EGF显像对肺癌荷瘤裸鼠化疗疗效的评价

目的探讨131I-EGF动态显像技术对肺癌倚瘤裸鼠化疗疗效的评价。方法将肺癌细胞株A549种植到BALB／cA—nil裸鼠体内,待移植瘤长至直径0．8～1．2cm时,随机分为4组：空白对照组、实验组（紫杉醇组、顺铂组和联合化疗组）。空白对照组腹腔注射0．1ml生理盐水;紫杉醇组腹腔注射紫杉醇5mg／kg;顺铂组腹腔注射ill@34rag／kg;联合化疗组腹腔注射紫杉醇5mg／kg和顺铂4mg／kg。裸鼠化疗后分别丁即刻和第7、14、21及28犬注射131I-EGF0．5h后开始显像,勾画感兴趣区（ROI）,计算肿瘤／健侧对应部位放射性（T／NT）比值,并测量肿瘤体积。第28天完成显像后,处死裸鼠,测量肿瘤／血液及肿瘤／肌肉放射性比值,计算抑瘤率和131I-EGF的生物学分布。结果肿瘤组织吸收131I-EGF较多,肿瘤／肌肉放射性比值对照组为5．65,高于联合化疗组（1．55,t=9．829,P〈0．01）、紫杉醇组（1．14,t=12．636,P〈0．01）和顺铂组（0．99,t=12．313,P〈0．01）。肿瘤／血液放射性比值对照组为3．15,高于联合化疗组（0．76,t=3．384,P〈0．05）、紫杉醇组（1．22,t=2．826,P〈0．05）和顺铂组（1．22,t=2．713,P〈0．05）。131I-EGF可使肿瘤组织清晰显像,联合化疗组肿瘤体积401．9mm3,与对照组（1134．2mm3）差异有统计学意义（t=9．393,P〈0．01）;紫杉醇组肿瘤体积634．73mm3（t=7．140,P〈0．01）,顺铂组肿瘤体积700．7mm3（t=6．820,P〈O．01）,这2组与对照组差异有统计学意义。各化疗组与对照组间T／NT比值差异有统计学意义（F=1011．251,P〈0．01）。结论化疗效果好的肿瘤,131I-EGF显像示肿瘤体积较小,瘤体内放射性分布较少;而化疗效果差的肿瘤体积逐渐增大,瘤体内放射性分布较多。131I-EGF显像可用于指导倚瘤裸鼠的化疗。     

Vitex Rotundifolia Fractions Induced Apoptosis in Human Breast Cancer T-47D Cell Line via Activation of Extrinsic and Intrinsic Pathway

Objective: Breast cancer is the most frequently diagnosed cancer worldwide. The main objective of the present study was to evaluate the cytotoxic effects and mechanism of cell death induced by the extract and fractions of Vitex rotundifolia (leaves) in breast cancer cell line, T-47D. Methods: The cytotoxicity activity was measured using MTS assay. The mode of cell death was analysed by early (phosphatidylserine externalization) and late apoptosis (DNA fragmentation). The caspases 8, 9, 3/7 and apoptotic proteins bax, bcl-2 study were done by western blot and ELISA method. Results: The methanol extract was found to inhibit 50% growth of T-47D cells at the concentration of 79.43µg/ml respectively after 72hr. From seven fractions, fraction F1, F2 and F3 produced cytotoxicity effects in T-47D cell line with IC50 (72hr) < 30µg/ml. The results obtained by Annexin V/PI apoptosis detection assay and TUNEL assay suggest that active fractions of  Vitex rotundifolia induced early and late apoptosis (DNA fragmentation) in T-47D cell line. Moreover, western blot analysis and Caspase GloTM luminescent assay demonstrated that fractions F2 and F3 triggered apoptotic cell death via activation of caspases -8, -9 and -3/7 and up-regulation of  Bax and down-regulation of Bcl-2 protein.  Furthermore, chemical profiling confirms the presence of potential metabolites (vitexicarpin) in fractions of Vitex rotundifolia. Conclusion: Thus, the present study suggests the remarkable potential of active metabolites in fractions of Vitex rotundifolia as future cancer therapeutic agent for the treatment of breast cancer.     

Chemosensitization and radiosensitization of human lung and colon cancers by antimitotic agent, ABT-751, in athymic murine xenograft models of subcutaneous tumor growth

Purpose

ABT-751 is an orally active antimitotic agent that is currently in Phase II clinical trials. This agent binds to the colchicine site on ß-tubulin and inhibits polymerization of microtubules. This disruption of microtubule dynamics leads to a block in the cell cycle at the G₂/M phase, and promotes apoptosis. ABT-751, as a single agent, has antitumor activity against a series of xenograft models including non-small cell lung cancer (NSCLC) and colon cancer. The current studies were conducted to determine whether ABT-751 enhances antitumor activity of standard cytotoxic therapies currently in clinical use.

Methods

Efficacy of ABT-751, in combination with cisplatin, 5-FU, and radiation, was evaluated in the Calu-6 NSCLC, HT-29 colon, and HCT-116 colon carcinoma xenograft models, respectively. Tumor-bearing athymic mice were treated with ABT-751 orally once a day at 75 or 100 mg/kg/day on a 5-days-on, 5-days-off schedule for two cycles.

Results

Efficacy of ABT-751 at 100 mg/kg/day was tested in combination with cisplatin at its maximum tolerable dose (MTD) (10 mg/kg/day, i.p. x1) in Calu-6 tumor-bearing athymic mice. The percent treated/control (%T/C) tumor volume ratios on day 38 were 35, 37, and 6, and the percent tumor growth delay (%TGD) values were 71, 65, and 188 for cisplatin, ABT-751 and the combination groups, respectively. HT-29 colon tumors were used to test ABT-751 in combination with an MTD of 5-FU, 30 mg/kg/day, i.p., q.d. x5. The %T/C ratios on day 38 were 22, 28, and 5 and the %TGD values were 75, 75, and 150 for 5-FU, ABT-751, and the combination groups, respectively. Treatment of HCT-116 colon carcinoma tumors with ABT-751, concurrent with the radiation treatment, was able to both enhance radiation-induced tumor regression, and delay the time to recurrence and progression. Growth curves allowed calculation of enhancement of radiation-induced growth delay (defined as the additional time required for a treated tumor to reach four times its original size) of 2, 9, and 12 days, for ABT-751 alone, radiation alone, and the combination, respectively.

Conclusion

Collectively, these studies demonstrate that ABT-751 enhanced efficacy of standard cytotoxic therapies in a variety of tumor xenograft models, and that enhancement was at least additive in all systems.     

The effect of various chemotherapeutic agents given with mild hyperthermia on different types of tumours

It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm 3 , a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5°C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm 3 from 65 mm 3 ) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5°C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5°C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.