低频率超声治疗实体肿瘤的临床研究及低频率超声和敏药碱逆转肿瘤多药耐药的体外研究
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摘要
低水平超声对恶性肿瘤的生物学效应的研究和应用仍处于研究阶段。一系列的研究显示恶性肿瘤细胞对低强度超声反应不同于正常细胞,因为肿瘤细胞更易被杀死。低强度超声可以抑制细胞的增殖和克隆形成,改善抗癌药物的作用,经过间接机制灭活肿瘤细胞。动物实验发现经低频超声辐射后的微泡剂能够引起肿瘤区域内的血管血栓形成及其周边的肿瘤组织坏死,甚至出血性坏死。这些发现显示低强度超声用于肿瘤的治疗有很大的潜力。由此,我们开展了以下工作:1、观察维生素C注射液+5%碳酸氢钠+706代血浆混合后产生的CO2微气泡的生物动力学特征。2、观察了低水平超声联合CO2微泡剂治疗晚期实体瘤的近期疗效和不良反应。3、用MTT法,免疫组化,PCR和流式细胞仪研究了低频率超声空化效应对多药耐药细胞株K562/ADM和MCF-7/ADM细胞耐药性的逆转作用。4、用MTT法,PCR和流式细胞仪研究了敏药碱对多药耐药细胞株K562/ADM和MCF-7/ADM细胞耐药性的逆转作用。结果证实:1、维生素C+碳酸氢钠+706代血浆混合后产生CO2微气泡直径大小与红细胞接近,稳定性较好,对人体安全无害,可以通过肺循环到达肝内静脉,增强了超声空化治疗肿瘤的作用。2、低频率超声空化治疗在临床治疗难治性实体瘤方面的疗效不低于全身化疗,与化疗联合可以提高疗效。3、单纯超声空化治疗在改善病人生活质量方面优于全身化疗,对于那些不能耐受全身化疗的患者,建议行低频超声空化治疗。4、超声空化效应毁损肿瘤微血管,减少肿瘤血液供应是其治疗肿瘤的主要机制。5、超声血管造影在监测肿瘤血管方面具有明显优势,值得临床应用和推广。6、低水平超声体外具有逆转MDR的活性,其逆转机制考虑为通过空化效应增加细胞膜的通透性,增加肿瘤细胞内抗肿瘤药物的浓度,促进肿瘤细胞凋亡;而并不是抑制MDR1基因和蛋白的表达。7、敏药碱可部分逆转人乳腺癌MCF-7/ADM细胞对ADM的耐药性,其逆转机制可能与抑制P-gp功能有关。
Objective: To investigate the biological dynamics and safety of the CO2microbubble from 5% sodium bicarbonate(NaHCO3)、vitamin C and 706 in vivoand vitro, the reversal effect of low-frequency ultrasound on the multi-drugresistance in K562/ADM and MCF-7/ADM and its possible mechanisms and alsowant to evaluate the effect of low-level ultrasound(US) on advanced solid tumor.Methods: The CO2 from 5% sodium bicarbonate、vitamin C and 706 wasobserved by microscope. The CO2 produced in intra-hepatic vessel and portalvessel was studied by Doppler ultrasound. We divided 48 patients into threegroups:A、B and C groups. Twenty patients in A group have ≥2 neoplasms;onegroup(A1) was treated by ultrasound and chemotherapy, the control group(A2)was treated by chemotherapy. Seventeen patients in B group were treated byultrasound treatment, and eleven patients in C group were treated bychemotherapy as control group of B. We evaluated the efficacy and side-effectafter 2 therapy circles and did contrast ultrasonography in 12 patients. The
change of tumor microvascularity before and after cavitation treatment wasobserved by ultrasound angiography. The effect of non-cytotoxic dose ofultrasound and minyaojian and the IC50 of ADM acted on K562/ADM andMCF-7/ADM was assessed by mehyl-hazol-etrazolinum (MTT)assay. Theexpression of p-gp was assessed by immunohistochemistry(IHC). MDR1 mRNAwas assessed by reversal transcription polymerase chain reaction(RT-PCR). Theapoptosis and concentration of intracellular drug were observed by flowcytometry(FCM). Results: After adding 706, the quantity of CO2 significantlyincreased, the diameter of CO2 is similar to that of red cell and the stability ofCO2 improved. The CO2 microbuble is safe and could arrive in intra-hepaticvessel and portal vessel through lung cycle. The signs of enchantment of contrastultrasonography responded less after cavitation treatment. As for efficacy,A1group is better than A2 group, B group is better than C group;but there was notsignificantly difference. The side-effect was higher in C group than B group.Comparing B with C, the quality of life in B group improved significantly. Aftercavitation treatment, 13 cases had PR, and the total effective rate was35.14%(13/37). And the signs level enchantment of contrast ultrasonographyresponded less to the cavitation treatment. MTT assay showed that the inhibitoryrate of K562/ADM and MCF7/ADM in US and US+CO2 group wassignificantly higher than the control group. Reverse multiple of US and US+CO2on K562/ADM was 2.34 and 3.97 respectively. Reverse multiple of US andUS+CO2 on MCF-7/ADM was 2.17 and 3.03 respectively. FCM suggested thatthe administration of low-frequency ultrasound combined with ADMsignificantly increased the apoptosis of K562/ADM and MCF7/ADM. Afterultrasound treatment, the expression of MDR1mRNA and P-gp had no
significantly change. The noncytotoxic dose of minyaojian was 10ug/ml.MTTassay showed that the inhibitory rate of K562/ADM and MCF7/ADM cell inminyaojian (F6,G2,G3) group was significantly higher than control group.Reverse multiple of F6,G2 and G3 on K562/ADM was 4.31,2.48 and 3.99respectively. Reverse multiple of F6,G2 and G3 on MCF-7/ADM was 2.06,1.58and 2.43 respectively.Rh123 retention test suggested that the administration ofmiyaojian combined with ADM increased the intracellular ADM concentration.After 10ug/ml minyaojian treatment,the expression of MDR1mRNA had nosignificantly change. Conclusions: The CO2 microbubble from 5% sodiumbicarbonate、vitaminC and 706 is a high quality contrast agent: its diameter issimilar to that of red cell, it is safe and could go through lung cycle, and enhanceanti-tumor effect of low-frequency ualtrasound, which is worthy of wide spreadin clinical application.Low-frequency ultrasound is able to enhance thecytotoxicity of ADM and partially reverse the ADM resistance of K562/ADMand MCF7/ADM. The mechanism maybe increase the permeability of cellmember and the concentration of intracellular ADM, promote the apoptosis ofK562/ADM and MCF7/ADM;but there was no effect on the mdr1 gene and p-gpexpression level. Minyaojian is able to enhance the cytotoxicity of ADM andpartially reverse the ADM resistance of K562/ADM and MCF-7/ADM, whichmay be relate to the inhibition of P-gp activity.The efficacy of cavitationtreatment is no less than system chemotherapy, combined with chemotherapy canraise the efficacy. Cavitation treatment can improves the quality of life of patientsand has low even no side-effects. The mechanism of cavitation treatment maybedestroy the tumor vessel. Ultrasound angiography can clearly indicate the changeof tumor microvascularity before and after cavitation treatment and could be used
in clinical tumor therapy.
Objective: To investigate the biological dynamics and safety of the CO2microbubble from 5% sodium bicarbonate(NaHCO3)、vitamin C and 706 in vivoand vitro, the reversal effect of low-frequency ultrasound on the multi-drugresistance in K562/ADM and MCF-7/ADM and its possible mechanisms and alsowant to evaluate the effect of low-level ultrasound(US) on advanced solid tumor.Methods: The CO2 from 5% sodium bicarbonate、vitamin C and 706 wasobserved by microscope. The CO2 produced in intra-hepatic vessel and portalvessel was studied by Doppler ultrasound. We divided 48 patients into threegroups:A、B and C groups. Twenty patients in A group have ≥2 neoplasms;onegroup(A1) was treated by ultrasound and chemotherapy, the control group(A2)was treated by chemotherapy. Seventeen patients in B group were treated byultrasound treatment, and eleven patients in C group were treated bychemotherapy as control group of B. We evaluated the efficacy and side-effectafter 2 therapy circles and did contrast ultrasonography in 12 patients. The
change of tumor microvascularity before and after cavitation treatment wasobserved by ultrasound angiography. The effect of non-cytotoxic dose ofultrasound and minyaojian and the IC50 of ADM acted on K562/ADM andMCF-7/ADM was assessed by mehyl-hazol-etrazolinum (MTT)assay. Theexpression of p-gp was assessed by immunohistochemistry(IHC). MDR1 mRNAwas assessed by reversal transcription polymerase chain reaction(RT-PCR). Theapoptosis and concentration of intracellular drug were observed by flowcytometry(FCM). Results: After adding 706, the quantity of CO2 significantlyincreased, the diameter of CO2 is similar to that of red cell and the stability ofCO2 improved. The CO2 microbuble is safe and could arrive in intra-hepaticvessel and portal vessel through lung cycle. The signs of enchantment of contrastultrasonography responded less after cavitation treatment. As for efficacy,A1group is better than A2 group, B group is better than C group;but there was notsignificantly difference. The side-effect was higher in C group than B group.Comparing B with C, the quality of life in B group improved significantly. Aftercavitation treatment, 13 cases had PR, and the total effective rate was35.14%(13/37). And the signs level enchantment of contrast ultrasonographyresponded less to the cavitation treatment. MTT assay showed that the inhibitoryrate of K562/ADM and MCF7/ADM in US and US+CO2 group wassignificantly higher than the control group. Reverse multiple of US and US+CO2on K562/ADM was 2.34 and 3.97 respectively. Reverse multiple of US andUS+CO2 on MCF-7/ADM was 2.17 and 3.03 respectively. FCM suggested thatthe administration of low-frequency ultrasound combined with ADMsignificantly increased the apoptosis of K562/ADM and MCF7/ADM. Afterultrasound treatment, the expression of MDR1mRNA and P-gp had no
significantly change. The noncytotoxic dose of minyaojian was 10ug/ml.MTTassay showed that the inhibitory rate of K562/ADM and MCF7/ADM cell inminyaojian (F6,G2,G3) group was significantly higher than control group.Reverse multiple of F6,G2 and G3 on K562/ADM was 4.31,2.48 and 3.99respectively. Reverse multiple of F6,G2 and G3 on MCF-7/ADM was 2.06,1.58and 2.43 respectively.Rh123 retention test suggested that the administration ofmiyaojian combined with ADM increased the intracellular ADM concentration.After 10ug/ml minyaojian treatment,the expression of MDR1mRNA had nosignificantly change. Conclusions: The CO2 microbubble from 5% sodiumbicarbonate、vitaminC and 706 is a high quality contrast agent: its diameter issimilar to that of red cell, it is safe and could go through lung cycle, and enhanceanti-tumor effect of low-frequency ualtrasound, which is worthy of wide spreadin clinical application.Low-frequency ultrasound is able to enhance thecytotoxicity of ADM and partially reverse the ADM resistance of K562/ADMand MCF7/ADM. The mechanism maybe increase the permeability of cellmember and the concentration of intracellular ADM, promote the apoptosis ofK562/ADM and MCF7/ADM;but there was no effect on the mdr1 gene and p-gpexpression level. Minyaojian is able to enhance the cytotoxicity of ADM andpartially reverse the ADM resistance of K562/ADM and MCF-7/ADM, whichmay be relate to the inhibition of P-gp activity.The efficacy of cavitationtreatment is no less than system chemotherapy, combined with chemotherapy canraise the efficacy. Cavitation treatment can improves the quality of life of patientsand has low even no side-effects. The mechanism of cavitation treatment maybedestroy the tumor vessel. Ultrasound angiography can clearly indicate the changeof tumor microvascularity before and after cavitation treatment and could be used
in clinical tumor therapy.
引文
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