WO2023185211A1 - 结肠癌治疗系统以及结肠癌治疗的交变电场发生装置 - Google Patents

结肠癌治疗系统以及结肠癌治疗的交变电场发生装置 Download PDF

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WO2023185211A1
WO2023185211A1 PCT/CN2023/071566 CN2023071566W WO2023185211A1 WO 2023185211 A1 WO2023185211 A1 WO 2023185211A1 CN 2023071566 W CN2023071566 W CN 2023071566W WO 2023185211 A1 WO2023185211 A1 WO 2023185211A1
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electric field
colon cancer
alternating electric
cancer treatment
platinum
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French (fr)
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卢健
周单
陈迪康
熊凌志
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湖南安泰康成生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36002—Cancer treatment, e.g. tumour

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  • the present invention relates to the field of tumor medical technology, and specifically to a colon cancer treatment system and an alternating electric field generating device for colon cancer treatment.
  • Colon cancer is a common gastrointestinal malignancy and the second leading cause of cancer-related deaths in humans.
  • the principle of colon cancer treatment is comprehensive treatment based on surgical resection, combined with chemotherapy, radiotherapy, etc. to reduce the recurrence rate after surgery and improve the survival rate.
  • neoadjuvant chemotherapy can be used for unresectable colon cancer.
  • it can reduce the tumor stage and convert some unresectable tumors into resectable tumors.
  • it can prolong the patient's survival time and improve the patient's quality of life.
  • Colon cancer gradually metastasizes to distant sites as it grows and develops. Three-quarters of patients already have metastases at the time of diagnosis. Among those who can undergo radical surgical resection, half of the patients eventually develop distant metastases.
  • Radiotherapy plays an important role in the treatment of colorectal cancer. It uses various types of radiation with different energies to irradiate tumors to kill tumor cells. Radiotherapy has a strong ability to kill cancer cells, and can have obvious effects in a short period of time, killing a large number of cancer cells and controlling the progression of the disease. Clinically, there are many patients whose tumors will shrink after radiotherapy, but it is unlikely to achieve the effect of tumor disappearance. Radiotherapy is only a local treatment, which can alleviate local symptoms of compression, but has no obvious inhibitory effect on cancer cells throughout the body. After radiotherapy, there are still residual cancer cells in the patient's body. These cancer cells will continue to grow and proliferate. When they reach a certain level, they can Get checked out.
  • radiotherapy is often used in combination with chemotherapy in clinical practice.
  • 5-fluorouracil 5FU
  • 5-fluorouracil 5FU
  • It has achieved good results in the clinical treatment of colorectal cancer when used alone or in combination with oxaliplatin.
  • the clinical benefits of chemotherapy are often short-lived, and patients who use chemotherapy are prone to develop resistance to it, resulting in a lower overall effectiveness and greatly reducing the effectiveness of chemotherapy.
  • Tumor electric field therapy is a new type of tumor treatment method. It uses externally applied electrodes to deliver an alternating electric field of medium frequency (100-300kHz) and low field strength (1-3Vpeak/cm) to the lesions in the body. Destroying rapidly dividing tumor cells is a new treatment method that is portable, effective and has low side effects. TTFields represent a new treatment approach that has been approved by the FDA for newly diagnosed glioblastoma and recurrent glioblastoma.
  • TTFields The basic principle of the action of TTFields is based on the fact that polar molecules in tumor cells are pulled by a medium-frequency, low-intensity alternating electric field, which blocks mitotic activity and ultimately leads to the death of tumor cells, while non-rapidly dividing cells and normal tissues are not affected. Influenced. TTFields is a physical rather than chemical modality that is well tolerated and has virtually no systemic side effects. The main side effect is localized contact dermatitis under the electrodes, which may be the result of a combination of factors. However, there is still a lot of room for improvement in the efficacy of TTFields. Targeted application of TTFields with specific parameters based on the patient's medication status will be an important technical way to improve the efficacy.
  • the first object of the present invention is to provide a colon cancer treatment system, which system includes:
  • Patient information processing module and output module
  • the sample information processing module is used to receive information about colon cancer patients treated with drugs.
  • the information at least includes medication information about the colon cancer patients receiving platinum-based chemotherapy drugs; the drugs are selected from platinum-based chemotherapy drugs, 5-fluorine One or more of uracil and capecitabine;
  • the output module is configured to receive information output by the patient information processing module and guide tumor electric field treatment for the colon cancer patient.
  • the second object of the present invention is to provide the use of one or more of platinum-based chemotherapy drugs, 5-fluorouracil and capecitabine in the preparation of colon cancer drugs;
  • the subjects of the colon cancer drug are colon cancer patients who have undergone tumor electric field treatment.
  • the third object of the present invention is to provide an alternating electric field generating device for colon cancer treatment, which includes an electrode, and when the electrode acts on a subject, it can apply alternating current to the subject's tumor cells.
  • Electric field the frequency of the alternating electric field is 150kHz to 250kHz, the field strength is ⁇ 1.5Vpeak/cm, and the intervention time of the alternating electric field is ⁇ 48h; the subject is a colon cancer patient and has undergone platinum-based chemotherapy drugs, 5-fluorine Treatment with one or more of uracil and capecitabine.
  • the present invention can inhibit the proliferation ability of colon cancer cells and promote cancer by applying one or more of platinum-based chemotherapy drugs, 5-fluorouracil and capecitabine to colon cancer cells and applying tumor electric field therapy to the cancer cells.
  • Cell apoptosis The data shows that the combination of the above drugs and tumor electric field therapy has a synergistic effect on the inhibition of proliferation of colon cancer cells.
  • the results confirm that the combination of the two is an effective treatment for colon cancer cells.
  • the combined use of 5-fluorouracil and electric fields has the effect Optimal, which provides a reference for improving the survival time of colon cancer patients.
  • Figure 1 shows the intervention effect of electric fields of different frequencies on HT29 cells provided by one embodiment of the present invention
  • Figure 2 shows the intervention effects of electric fields of different frequencies on CT26 cells provided by an embodiment of the present invention
  • Figure 3 shows the intervention effect of electric fields at different times on HT29 cells provided by one embodiment of the present invention
  • Figure 4 shows the intervention effect of electric fields at different times on CT26 cells provided by one embodiment of the present invention
  • Figure 5 shows the intervention effect of electric fields of different field strengths on HT29 cells provided by one embodiment of the present invention
  • Figure 6 shows the intervention effects of electric fields of different field strengths on CT26 cells provided by one embodiment of the present invention
  • Figure 7 shows the effects of different groups of treatment methods on the apoptosis of colon cancer cells using flow cytometry statistics according to one embodiment of the present invention
  • Figure 8 shows the effects of different groups of treatment methods on the viability of colon cancer cells provided by an embodiment of the present invention.
  • A is 5-fluorouracil
  • B is capecitabine
  • C is oxaliplatin.
  • the technical solution of "A, and/or, B, and/or, C, and/or, D” includes any one of A, B, C, and D (that is, they are all connected with "logical OR” technical solution), also includes any and all combinations of A, B, C, and D, that is, including combinations of any two or any three of A, B, C, and D, and also includes A, B, C , four combinations of D (that is, technical solutions that are all connected by "logical AND").
  • patient refers to a mammal suffering from colon cancer, such as cats, dogs, cattle, sheep, horses, etc. Primates are preferred, and humans are more preferred.
  • drug specifically refers to one or more of platinum-based chemotherapy drugs, 5-fluorouracil and capecitabine.
  • Treatment used in the present invention means improving, inhibiting or delaying the growth and recurrence of the patient's tumor during the chemotherapy period, inhibiting metastasis, and prolonging the patient's survival time.
  • At least one symptom or side effect has developed, further progression of the side effect is slowed, and/or the side effect is alleviated.
  • the present invention refers to concentration values, and their meaning includes fluctuations within a certain range. For example, it can fluctuate within the corresponding accuracy range. For example, 2% can allow fluctuation within the range of ⁇ 0.1%. For values that are large or do not require too fine control, the meaning is also allowed to include larger fluctuations. For example, 100mM can allow fluctuations within the range of ⁇ 1%, ⁇ 2%, ⁇ 5%, etc. Referring to molecular weight, fluctuations of ⁇ 10% are allowed.
  • the technical features described in open terms include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.
  • the present invention relates to a colon cancer treatment system, which system includes:
  • Patient information processing module and output module
  • the sample information processing module is used to receive information about colon cancer patients treated with drugs.
  • the information at least includes medication information about the colon cancer patients receiving the drugs; the drugs are selected from platinum-based chemotherapy drugs and 5-fluorourea.
  • the output module is configured to receive information output by the patient information processing module and guide tumor electric field treatment for the colon cancer patient.
  • tumor electric field treatment is carried out in accordance with the methods well known to those skilled in the art in the prior art.
  • all electrodes are positioned on the subject's body; in other embodiments, all electrodes can be implanted within the subject's body (e.g., just beneath the subject's skin, or in the vicinity of the organ being treated); and in other embodiments, some of the electrodes are positioned on the subject's skin while the remaining electrodes are implanted within the subject's body.
  • the drug is administered directly to the cells.
  • the drug may be administered to the cell indirectly (e.g., in the form of a prodrug that is converted to the drug in the subject).
  • a precursor, prodrug prodrug, prodrug, or different drug may be advantageous to administer a precursor, prodrug prodrug, prodrug, or different drug to a subject by reducing side effects or altering pharmacokinetics in a desirable manner.
  • indirectly administered ingredients can be converted into the drug in the body (eg, the liver).
  • the electric field used for tumor electric field treatment is an alternating electric field.
  • the output module is used to adjust the frequency of the alternating electric field to 150 kHz to 250 kHz, such as 160 kHz, 170 kHz, 180 kHz, 190 kHz, 200 kHz, 210 kHz, 220 kHz, 230 kHz, and 240 kHz.
  • the optimal frequency can be determined for each individual's own circumstances (such as sensitivity and tolerance to frequency). Preferably, care is taken to ensure that the alternating electric field at the selected frequency does not adversely heat parts of the subject's body.
  • the output module is used to adjust the field strength of the alternating electric field to ⁇ 1.5Vpeak/cm, such as 1.5Vpeak/cm ⁇ 2.5Vpeak/cm, such as 1.6Vpeak/cm, 1.7Vpeak/cm, 1.8 Vpeak/cm, 1.9Vpeak/cm, 2.0Vpeak/cm, 2.0Vpeak/cm, 2.1Vpeak/cm, 2.2Vpeak/cm.
  • the output module is used to adjust the field strength of the alternating electric field to ⁇ 2.2Vpeak/cm, such as 2.3Vpeak/cm, 2.4Vpeak/cm, or 2.5Vpeak/cm.
  • the noted field strength values of the alternating electric field are the maximum amplitude (E p ) within a single cycle of the AC signal.
  • care is taken to ensure that the alternating electric field at the selected field strength does not adversely heat parts of the subject's body.
  • the intervention time of the output module for adjusting the alternating electric field is ⁇ 48h, such as 48h to 82h, such as 52h, 56h, 60h, 64h, 64h, 68h.
  • the intervention time of the output module for adjusting the alternating electric field is ⁇ 72h, such as 76h, 80h.
  • the intervention time can be continuous or interval (but the cumulative time should reach the above intervention time). For example, when the total intervention time is 72 hours, the intervention can be delivered in 6 sessions of 12 hours each with a 2-hour interval between sessions.
  • the term "interval" refers to a time interval in which no electric field is applied. Here again preferably care is taken to ensure that the alternating electric field at the selected intervention time does not adversely heat parts of the subject's body.
  • the above-mentioned parameters of the alternating electric field are all set for the target area, especially the area that acts on tumor cells and nearby tissues.
  • Platinum-based chemotherapy drugs work in a similar way. These agents do not have alkyl groups, yet still damage DNA. They permanently coordinate with DNA to interfere with DNA repair, hence their description as "alkylation-like".
  • platinum analogs of the present invention are one or more of the following: platinum, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, and triplatinum tetranitrate.
  • At least a portion of the tumor electric field treatment is performed after said administration of the drug and before elimination of the drug from the subject's body.
  • the term "elimination from a subject's body” means, for example, (1) metabolism of one or more of the drugs in the liver or elsewhere in the body, resulting in the elimination of substantially all of the one or more drugs from the body , or (2) reducing the concentration of one or more of the drugs in the subject's bloodstream such that the drugs no longer provide substantially all of their therapeutic effect.
  • substantially as used herein means greater than about 50%, 60%, 70%, 80%, 90% or 100%.
  • the medication information includes one or more of the type of drug, administration method, administration start and end time, and side effects after medication.
  • the most common side effects of chemotherapy include nausea, vomiting, diarrhea or constipation, weakness, fatigue, mucositis, hair loss, respiratory and cognitive impairment.
  • the electric field strength can be adjusted as appropriate based on the severity of side effects.
  • the information also includes the patient's photo, age, gender, height, weight, ethnicity, eating habits, medication history, mood status, time from symptom onset to treatment, family genetic history, religious beliefs, smoking One or more of frequency, exercise type and frequency.
  • the present invention also relates to the use of one or more of platinum-based chemotherapy drugs, 5-fluorouracil and capecitabine in the preparation of colon cancer drugs;
  • the subjects of the colon cancer drug are colon cancer patients who have undergone tumor electric field treatment.
  • an alternating electric field generating device for colon cancer treatment which includes an electrode, and when the electrode acts on a subject, it is capable of applying force to the subject's tumor cells.
  • Alternating electric field the frequency of the alternating electric field is 150kHz ⁇ 250kHz, the field strength is ⁇ 1.5Vpeak/cm, and the intervention time of the alternating electric field is ⁇ 48h; the subject is a colon cancer patient and has undergone platinum-based chemotherapy drugs, 5 -Treatment with one or more of fluorouracil and capecitabine.
  • the present invention also relates to a method of treating colon cancer in a subject, the method comprising: administering to the subject one or more of a platinum-based chemotherapy drug, 5-fluorouracil, and capecitabine ; and applying an alternating electric field to a target area of the subject.
  • the preferred frequency of the alternating electric field is 150 kHz to 250 kHz.
  • the preferred field strength of the alternating electric field is ⁇ 1.5Vpeak/cm.
  • the preferred intervention time of the alternating electric field is ⁇ 48 hours.
  • the alternating electric field is as described above.
  • the measurement parameters of raw material components are involved. Unless otherwise specified, there may be slight deviations within the range of weighing accuracy. Temperature and time parameters are involved, allowing for acceptable deviations due to instrument testing accuracy or operating accuracy.
  • the colon cancer cell line (HT-29/CT-26, purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences) was used to test the effects of electric fields and 5-fluorouracil (5FU) or oxaliplatin or capecitabine alone or in combination. effect. All cells were grown in a humidified cell culture incubator supplied with 5% CO2 .
  • the cell culture medium was purchased from Gibco Company, and 10% fetal bovine serum and 1% penicillin and streptomycin were added before culturing cells.
  • alternating electric fields 100-300kHz, 1-3Vpeak/cm
  • the cells were divided into two groups, one group with electric field applied and one group without electric field.
  • the electric field adding group adjusted the electric field parameters of the instrument to the required frequency according to the experimental conditions, and set the corresponding cell culture incubator temperature according to different frequency parameters to ensure that the temperature in the quadrilateral culture dish was always maintained at 37°C during the entire power-on process.
  • the electric field action time is 24h-72h. After the electric field treatment, all slides were taken out, digested with trypsin, and made into cell suspension for cell counting and subsequent experiments. The experiment was repeated three times.
  • the cell line HT-29 was used, the frequency was 200kHz, the field strength was 2.2Vpeak/cm, and the electric field treatment time was 72h.
  • the concentration of oxaliplatin was 40 mg/L, the concentration of 5FU was 10 mg/L, and the concentration of capecitabine was 200 mg/L. They were administered simultaneously during the electric field treatment.
  • CCK-8 cell viability detection kit contains WST-8(2-(2-methoxy-4-niphenyl)-3-(4-niphenyl)-5-(2,4-disulfobenzene) )-2H-tetrazole monosodium salt), in the presence of electron carriers, WST-8 is oxidized and reduced by intracellular dehydrogenase to generate a water-soluble orange-yellow formazan dye, which can be dissolved in tissue culture medium, and the generated formazan dye The volume is directly proportional to the number of viable cells.
  • the CCK-8 method is a highly sensitive, non-radioactive colorimetric detection method used to determine the number of viable cells in cell experiments. Collect the above cell suspension, add 10ul CCK-8 solution to each well, continue to incubate in the cell culture incubator for 1.5 to 2 hours, and measure the absorbance of each well at 450nm with a microplate reader.
  • Collect cells resuspend 1 ⁇ 10 5 cells in 200 ⁇ L Binding Buffer, add 4 ⁇ L 0.5 mg/mL PI and 2 ⁇ L Annexin V-FITC solution, incubate at room temperature for 15 min in the dark, and perform fluorescence detection with a flow cytometer.
  • the control field strength is 2.2Vpeak/cm
  • the electric field action time is 72h
  • HT-29/CT-26 cells are treated with AC electric field frequencies of 0kHz, 100kHz, 200kHz, and 300kHz respectively, and the cell proliferation is detected.
  • the experimental results are shown in Figures 1 and 2. The results show that the 200kHz electric field is the optimal frequency for two different colon cancer cell lines.
  • the control field strength is 2.2Vpeak/cm
  • the AC electric field frequency is 200kHz
  • the HT-29/CT-26 cells are treated with AC electric field exposure times of 0h, 24h, 48h, and 72h respectively, and the cell proliferation is detected.
  • the experimental results in Figures 3 and 4 show that the inhibitory effect of electric fields on colon cancer cell lines is positively correlated with the intervention time. The longer the electric field action time, the better the inhibitory effect.
  • the AC electric field frequency is controlled to 200kHz
  • the electric field action time is 72h
  • HT-29/CT- is treated with AC electric field strengths of 0Vpeak/cm, 1.0Vpeak/cm, 1.5Vpeak/cm, and 2.2Vpeak/cm. 26 cells, and detect cell proliferation.
  • the experimental results in Figures 5 and 6 show that the greater the intensity of the electric field, the more significant the effect of inhibiting cell proliferation.
  • the cell line HT-29 was used, the frequency was 200kHz, the field strength was 2.2Vpeak/cm, and the electric field treatment time was 24h.
  • the concentration of oxaliplatin is 40 mg/L, and oxaliplatin is administered while applying the electric field.
  • Figure 7 and Table 1 illustrate that cell apoptosis was detected by flow cytometry. Compared with the control group, the cell apoptosis rate in the electric field combined with oxaliplatin group increased from 1.54% to 8.7%, and the results were statistically different.
  • the cell line HT-29 was used, the frequency was 200kHz, the field strength was 2.2Vpeak/cm, and the electric field treatment time was 24h.
  • the drugs were selected as oxaliplatin or 5FU or capecitabine respectively.
  • the concentration of oxaliplatin was 40 mg/L, the concentration of 5FU was 10 mg/L, and the concentration of capecitabine was 200 mg/L. Treatments were administered simultaneously during electric field treatment.
  • Figure 8 Experimental results show that compared with the use of oxaliplatin, 5FU, or capecitabine alone, the combined use of electric fields and oxaliplatin, 5FU, or capecitabine significantly differentially reduced the viability of colon cancer cells. Compared with the use of 5FU alone, the combination of electric field and 5FU reduced the cell viability from 67.78% to 28.71%; compared with the use of capecitabine alone, the combination of electric field and capecitabine reduced the cell viability from 70.29% to 53.12%; Compared with oxaliplatin alone, the combination of electric field and oxaliplatin reduced cell viability from 45.73% to 24.10%.

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Abstract

本发明涉及肿瘤医疗技术领域，具体而言，涉及结肠癌治疗系统以及结肠癌治疗的交变电场发生装置。该系统包括：患者信息处理模块以及输出模块；所述样本信息处理模块用于接收采用药物治疗的结肠癌患者信息，所述信息至少包括所述结肠癌患者接受所述药物的用药信息；所述药物选自铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种；所述输出模块用于接收所述患者信息处理模块输出的信息，并指导对所述结肠癌患者的肿瘤电场治疗。

Description

结肠癌治疗系统以及结肠癌治疗的交变电场发生装置
相关申请的交叉引用
本申请要求于2022年03月28日提交中国专利局的申请号为202210314367.5、名称为“结肠癌治疗系统以及结肠癌治疗的交变电场发生装置”的中国专利申请的优先权，并将其全部内容通过引用结合在本申请中。
技术领域
本发明涉及肿瘤医疗技术领域，具体而言，涉及结肠癌治疗系统以及结肠癌治疗的交变电场发生装置。
背景技术
结肠癌是一种常见的胃肠道恶性肿瘤，是造成人类癌症相关死亡的第二大原因。结肠癌治疗原则是以手术切除为主的综合治疗，同时联合化疗、放疗等降低手术后复发率，提高生存率。对于不能切除的结肠癌，可采取新辅助化疗，一方面可以降低肿瘤的分期，使部分不能切除的肿瘤转化为能够切除的肿瘤；另一方面可延长患者的生存时间，提高患者的生存质量。结肠癌随着生长发育逐渐向远处转移，有3/4的患者在诊断时就已经有转移，能够接受根治性手术切除者，也有半数患者最终发生远处转移。
放疗在结直肠癌的治疗中占据着重要的地位，是利用各种能量不同的放射线照射肿瘤，达到杀灭肿瘤细胞的目的。放疗对于癌细胞有较强的杀伤能力，可以在短期内看到明显的效果，杀死大量的癌细胞，控制病情发展。临床上有很多患者经放疗后，肿块会有所缩小，但是想要达到肿瘤消失的效果可能性不大。放疗只是局部治疗，可以减轻局部压追症状，但对 全身的癌细胞没有明显的抑制作用，患者经放疗后体内仍然有残存的癌细胞，这些癌细胞会继续生长增殖，当到达一定程度上才能被检查出来。
因此，针对放疗的局限性，临床上放疗多与化疗联合使用。如，5-氟脲嘧啶(5Fluorouracil，5FU)作为胃肠道恶性肿瘤的常用治疗药物，单用或联合奥沙利铂用在结直肠癌的临床治疗中取得良好效果。然而，化疗的临床获益往往是短暂的，使用化疗的患者易对其产生耐药性而使得总体有效率较低，大大降低化疗效果。
肿瘤电场治疗(TTFields)是一种新型的肿瘤治疗方法，它通过体外贴敷式电极片，向体内病灶传递中频(100-300kHz)、低场强(1-3Vpeak/cm)的交变电场，破坏处于快速分裂状态的肿瘤细胞，是一种便携、有效、低副反应的新型治疗方式。TTFields代表了一种新的治疗方法，已经被FDA批准用于新诊断的胶质母细胞瘤和复发性胶质母细胞瘤等。
TTFields作用的基本原理，是基于肿瘤细胞内极性分子受中频、低强度的交变电场所牵拉，有丝分裂活动受阻，并最终导致肿瘤细胞死亡，而对非快速分裂细胞和正常组织是不受影响的。TTFields是一种物理而非化学的模式，这种治疗方式耐受性良好，几乎没有任何全身系统性毒副作用。主要的副作用是电极下的局部接触性皮炎，这种反应可能是多种因素综合作用的结果。然而，目前TTFields的疗效仍有很大的改善空间，根据患者用药情况，有针对性地施加特定参数的TTFields，将是提高疗效的重要技术路径。
发明内容
本发明的第一目的在于提供一种结肠癌治疗系统，所述系统包括：
患者信息处理模块以及输出模块；
所述样本信息处理模块用于接收采用药物治疗的结肠癌患者信息，所述信息至少包括所述结肠癌患者接受铂基化疗药物的用药信息；所述药物 选自铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种；
所述输出模块用于接收所述患者信息处理模块输出的信息，并指导对所述结肠癌患者的肿瘤电场治疗。
本发明的第二目的在于提供铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种在制备结肠癌药物中的应用；
所述结肠癌药物的受试者为经过肿瘤电场治疗的结肠癌患者。
本发明的第三目的在于提供一种用于结肠癌治疗的交变电场发生装置，其包括电极，当所述电极作用于受试者时，能够对所述受试者的肿瘤细胞施加交变电场，所述交变电场的频率为150kHz～250kHz，场强≥1.5Vpeak/cm，交变电场的干预时间≥48h；所述受试者为结肠癌患者且经过铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种药物治疗。
本发明通过向结肠癌细胞施用铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种并向癌细胞施加肿瘤电场治疗，可以抑制结肠癌细胞的增殖能力以及促进癌细胞的凋亡。数据表明上述药物和肿瘤电场治疗的组合对结肠癌细胞的增殖抑制产生协同效应，所述结果证实了二者组合是针对结肠癌细胞的有效治疗，其中，5-氟脲嘧啶与电场联合使用效果最佳，这为提高结肠癌患者生存期提供了参考依据。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明一个实施例所提供的不同频率的电场对HT29细胞的干预 效果；
图2为本发明一个实施例所提供的不同频率的电场对CT26细胞的干预效果；
图3为本发明一个实施例所提供的不同时间的电场对HT29细胞的干预效果；
图4为本发明一个实施例所提供的不同时间的电场对CT26细胞的干预效果；
图5为本发明一个实施例所提供的不同场强的电场对HT29细胞的干预效果；
图6为本发明一个实施例所提供的不同场强的电场对CT26细胞的干预效果；
图7为本发明一个实施例所提供的采用流式细胞法统计的不同组别处理方式对结肠癌细胞凋亡的影响；
图8为本发明一个实施例所提供的不同组别处理方式对结肠癌细胞的活力的影响；A为5-氟脲嘧啶；B为卡培他滨；C为奥沙利铂。
具体实施方式
现将详细地提供本发明实施方式的参考，其一个或多个实例描述于下文。提供每一实例作为解释而非限制本发明。实际上，对本领域技术人员而言，显而易见的是，可以对本发明进行多种修改和变化而不背离本发明的范围或精神。例如，作为一个实施方式的部分而说明或描述的特征可以用于另一实施方式中，来产生更进一步的实施方式。
除非另有说明，用于披露本发明的所有术语(包括技术和科学术语)的意义与本发明所属领域普通技术人员所通常理解的相同。通过进一步的指导，随后的定义用于更好地理解本发明的教导。本文中在本发明的说明书中所 使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
本文所使用的术语“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列项目中任一个项目，也包括相关所列项目的任意的和所有的组合，所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是，当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时，应当理解，在本申请中，该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案，还毫无疑问地包括均用“逻辑或”连接的技术方案。比如，“A及/或B”包括A、B和A+B三种并列方案。又比如，“A，及/或，B，及/或，C，及/或，D”的技术方案，包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案)，也包括A、B、C、D的任意的和所有的组合，也即包括A、B、C、D中任两项或任三项的组合，还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本发明中所使用的术语“含有”、“包含”和“包括”是同义词，其是包容性或开放式的，不排除额外的、未被引述的成员、元素或方法步骤。
本发明中用端点表示的数值范围包括该范围内所包含的所有数值及分数，以及所引述的端点。
本发明中“患者”或“受试者”指患有结肠癌的哺乳动物，例如猫、犬、牛、羊、马等，优选灵长类动物，更优选为人。
本发明中，为以示区别，术语“药物”专指铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种。
本发明中所用的“治疗”表示改善、抑制或延缓患者在化疗期内肿瘤生长与复发进展、抑制转移、延长患者生存时间。
已发展至少一种症状或副作用，该副作用的进一步进展被减缓和/或该副作用被缓解。
本发明中涉及浓度数值，其含义包括在一定范围内的波动。比如，可 以在相应的精度范围内波动。比如2％，可以允许±0.1％范围内波动。对于数值较大或无需过于精细控制的数值，还允许其含义包括更大波动。比如100mM，可以允许±1％、±2％、±5％等范围内的波动。涉及分子量，允许其含义包括±10％的波动。
本发明中，涉及“多个”、“多种”等描述，如无特别限定，指在数量上指大于等于2。
本发明中，以开放式描述的技术特征中，包括所列举特征组成的封闭式技术方案，也包括包含所列举特征的开放式技术方案。
本发明中，“优选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例，应当理解，并不构成对本发明保护范围的限制。本发明中，“可选地”、“可选的”、“可选”，指可有可无，也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“可选”各自独立。
本发明涉及一种结肠癌治疗系统，所述系统包括：
患者信息处理模块以及输出模块；
所述样本信息处理模块用于接收采用药物治疗的结肠癌患者信息，所述信息至少包括所述结肠癌患者接受所述药物的用药信息；所述药物选自铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种；
所述输出模块用于接收所述患者信息处理模块输出的信息，并指导对所述结肠癌患者的肿瘤电场治疗。
本发明中肿瘤电场治疗依照现有技术中本领域技术人员所熟知的方式进行。在一些实施例中，所有电极都被定位在受验者的身体上；在其他实施例中，所有电极都可以被植入受验者的身体内(例如，刚好在受验者的皮肤下方，或者在被治疗的器官的附近)；以及在其他实施例中，电极中的一些被定位在受验者的皮肤上，而其余的电极被植入受验者的身体内。
在某些情况下，所述药物向细胞直接施用。在其它情况下，可以将所 述药物间接地施用给细胞(例如以前药前体的形式施用，在受试者的体内转化成所述药物)。
在某些情况下，通过以合乎需要的方式减少副作用或改变药代动力学，向受试者施用前体、前药前体、前药或不同的药物可以是有利的。通常的，间接施用的成分可以在身体(例如，肝脏)中转化成所述药物。
在一些实施方式中，所述肿瘤电场治疗所用电场为交变电场。
在一些实施方式中，所述输出模块用于调整所述交变电场的频率为150kHz～250kHz，例如160kHz、170kHz、180kHz、190kHz、200kHz、210kHz、220kHz、230kHz、240kHz。
可以针对每个个体自身情况(例如对频率的敏感与耐受程度)确定最佳频率。优选地，注意确保选择的频率处的交变电场不会不利地加热受验者的身体的部位。
在一些实施方式中，所述输出模块用于调整所述交变电场的场强≥1.5Vpeak/cm，例如1.5Vpeak/cm～2.5Vpeak/cm，例如1.6Vpeak/cm、1.7Vpeak/cm、1.8Vpeak/cm、1.9Vpeak/cm、2.0Vpeak/cm、2.0Vpeak/cm、2.1Vpeak/cm、2.2Vpeak/cm。
在一些实施方式中，所述输出模块用于调整所述交变电场的场强为≥2.2Vpeak/cm，例如2.3Vpeak/cm、2.4Vpeak/cm、2.5Vpeak/cm。
在本发明中，若非特别强调，则所注明交变电场的场强值均为交流信号单个周期内的最大幅值(E p)。
这里再次优选地注意确保选择的场强处的交变电场不会不利地加热受验者的身体的部位。
在一些实施方式中，所述输出模块用于调整所述交变电场的干预时间≥48h，例如48h～82h，例如52h、56h、60h、64h、64h、68h。
在一些实施方式中，所述输出模块用于调整所述交变电场的干预时间 ≥72h，例如76h、80h。
干预时间可以为连续或间隔进行(但累积时间应达到上述干预时间)的。例如，当总干预时间为72小时时，可以以6个具有各12小时的持续时间的期间进行干预，在期间之间具有2小时间隔。术语“间隔”是指其中不施加电场的时间区间。这里再次优选地注意确保选择的干预时间处的交变电场不会不利地加热受验者的身体的部位。
上述交变电场的参数均是针对靶区域所设定的，特别是指作用应肿瘤细胞及其附近组织的区域。
铂基化疗药物(称作铂类似物)以类似方式起作用。这些药剂不具有烷基，然而还是破坏DNA。它们永久性地与DNA配位以干扰DNA修复，因此将它们描述为“类烷化”。本发明中铂类似物的一些非限制性实例是以下中的一种或多种：铂、顺铂、卡铂、奈达铂、奥沙利铂、沙铂和四硝酸三铂。
在某些情况下，在所述施用药物之后并在药物从受试者的身体消除之前进行肿瘤电场治疗的至少一部分。术语“从受试者的身体消除”是指，例如，(1)一种或多种所述药物在肝脏或体内别处的代谢，导致基本上所有的一种或多种所述药物从体内排出，或(2)降低受试者的血流中的一种或多种所述药物的浓度，使得所述药物不再提供基本上所有的其治疗效果。本文中使用的术语“基本上”是指大于约50％、60％、70％、80％、90％或100％。
在一些实施方式中，所述用药信息包括所述药物的种类、给药方式、给药起止时间、用药后的副作用中的一种或多种。
化疗最常见的用药后的副作用包括恶心、呕吐、腹泻或便秘、虚弱、疲劳、粘膜炎、脱发、呼吸和认知障碍。可通过副作用的严重情况酌情调整电场强度。
在一些实施方式中，所述信息还包括所述患者的照片、年龄、性别、身高、体重、民族、饮食习惯、用药史、心情状况、出现症状至就诊时间、家族遗传病史、宗教信仰、吸烟频次、运动类型及频次中的一项或多项。
根据本发明的再一方面，还涉及铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种在制备结肠癌药物中的应用；
所述结肠癌药物的受试者为经过肿瘤电场治疗的结肠癌患者。
根据本发明的再一方面，还涉及一种用于结肠癌治疗的交变电场发生装置，其包括电极，当所述电极作用于受试者时，能够对所述受试者的肿瘤细胞施加交变电场，所述交变电场的频率为150kHz～250kHz，场强≥1.5Vpeak/cm，交变电场的干预时间≥48h；所述受试者为结肠癌患者且经过铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种药物治疗。
本发明还涉及一种治疗受试者中的结肠癌的方法，所述方法包括：将铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种施用给受试者；和将交变电场施加于受试者的靶区域。
所述交变电场优选的频率为150kHz～250kHz。
所述交变电场优选的场强≥1.5Vpeak/cm。
所述交变电场优选的干预时间≥48h。
在一些实施方式中，所述交变电场如上文中所述。
下面将结合实施例对本发明的实施方案进行详细描述。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，优先参考本发明中给出的指引，还可以按照本领域的实验手册或常规条件，还可以参考本领域已知的其它实验方法，或者按照制造厂商所建议的条件。
下述的具体实施例中，涉及原料组分的量度参数，如无特别说明，可能存在称量精度范围内的细微偏差。涉及温度和时间参数，允许仪器测试精度或操作精度导致的可接受的偏差。
实施例
1、实验方法：
采用结肠癌细胞系(HT-29/CT-26，购自中科院上海细胞库)，测试了电场和5-氟脲嘧啶(5FU)或奥沙利铂或卡培他滨的单独或联合处理的效应。所有细胞都在提供有5％CO 2的加湿细胞培养箱中生长。细胞培养基购买于Gibco公司，用于培养细胞前加入10％胎牛血清和1％的青霉素与链霉素。
细胞增殖检测
用交变电场(100-300kHz、1-3Vpeak/cm)干预结肠癌细胞。制备细胞悬液，调节细胞浓度。将直径为
Figure PCTCN2023071566-appb-000001
玻片置于陶瓷培养皿中，并使用体外细胞实验肿瘤电场干预设备。每片玻片加100-150ul细胞悬液，使细胞悬液均匀分布于玻片表面。置于37℃饱和湿度培养箱中4-6h待细胞完全贴壁后，补充培养基4ml，置于37℃饱和湿度培养箱中培养过夜。将细胞分为两组，一组施加电场，一组不加电场。加电场组根据实验条件，将仪器的电场参数调至所需频率，且根据不同频率参数设置相对应的细胞培养箱温度，以确保整个通电过程中四边形培养皿内温度始终保持37℃。电场作用时间24h-72h。电场处理完后取出所有玻片，加入胰酶消化，制成细胞悬液，进行细胞计数及后续实验。实验重复3次。
电场强度测量方式
培养皿中添加培养液后，给培养皿施加电场，取两根探针随机插入培养皿中心两点，用示波器测量探针间的电压信号，读取电压信号峰值，记为V p，用游标卡尺测量两探针间的间距，记为d，则探针尖端中心连线的中点电场强度为E p＝V p/d，还可以通过调整探针位置，重复测量多次，取多次测量的平均值作为最终值。
CCK-8细胞活力检测
实验设置：采用细胞系HT-29,频率200kHz,场强2.2Vpeak/cm,电场处理时间72h。奥沙利铂浓度为40mg/L,5FU浓度为10mg/L,卡培他滨浓度为200mg/L，电场处理期间同时给药治疗。
CCK-8细胞活力检测试剂盒含有WST-8(2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺基苯)-2H-四唑单钠盐)，在电子载体存在的情况下WST-8被细胞内脱氢酶氧化还原后生成水溶性的橙黄色甲臜染料能够溶解在组织培养基中，生成的甲臜量与活细胞数量成正比。CCK-8法是用于测定细胞实验中活细胞数目的一种高灵敏度、无放射性的比色检测法。收集上述细胞悬液，每孔加入10ul CCK-8溶液，在细胞培养箱内继续孵育1.5～2小时后，酶标仪于450nm测定每孔吸光度。
细胞凋亡检测(流式细胞术)
收集细胞，将1×10 5个细胞重悬于200μL Binding Buffer中，加入4μL0.5mg/mL PI和2μL Annexin V-FITC溶液，避光室温孵育15min，用流式细胞仪进行荧光检测。
实验数据用Graphpad Prism软件进行统计分析，组间比较采用t检验，所有数据以均数±标准差表示，*或#P＜0.05，**或##P＜0.01，***或###P＜0.001。*代表各实验组与对照组统计学比较，#代表各实验组之间统计学比较。
2、实验结果
2.1电场干预结肠癌细胞增殖具有频率(kHz)依赖性
按照上述实验方法，控制场强是2.2Vpeak/cm，电场作用时间是72h，分别以0kHz、100kHz、200kHz、300kHz的交流电场频率处理HT-29/CT-26细胞，并检测细胞增殖情况。实验结果如图1和图2所示，结果表明200kHz电场均为两种不同结肠癌细胞系的最佳频率。
2.2电场干预结肠癌细胞增殖具有时间(h)依赖性
按照上述实验方法，控制场强是2.2Vpeak/cm，交流电场频率是200kHz，分别以0h、24h、48h、72h的交流电场作用时间处理HT-29/CT-26细胞，并检测细胞增殖情况。图3、4实验结果表明电场对结肠癌细胞系的抑制效果与干预时间成正相关，电场作用时间越长，抑制效果越好。
2.3电场干预结肠癌细胞增殖具有场强(V/cm)依赖性
按照上述实验方法，控制交流电场频率是200kHz，电场作用时间是72h，分别以0Vpeak/cm、1.0Vpeak/cm、1.5Vpeak/cm、2.2Vpeak/cm的交流电场场强处理HT-29/CT-26细胞，并检测细胞增殖情况。图5、6实验结果表明电场场强越大，抑制细胞增殖作用效果越显著。
2.4电场促进了奥沙利铂诱导的结肠癌细胞的凋亡
实验设置：采用细胞系HT-29，频率200kHz，场强2.2Vpeak/cm，电场处理时间24h。奥沙利铂浓度为40mg/L，加电场的同时给与奥沙利铂。
图7与表1说明通过流式细胞术检测细胞凋亡，电场联合奥沙利铂组与对照组相比，细胞凋亡率从1.54％提高到了8.7％，且结果具有统计学差异。
表1
Figure PCTCN2023071566-appb-000002
2.5电场联合奥沙利铂或5FU或卡培他滨显著差异性降低了结肠癌细胞的活力
实验设置：采用细胞系HT-29，频率200kHz，场强2.2Vpeak/cm，电场处理时间24h。药物分别选用奥沙利铂或5FU或卡培他滨，奥沙利铂浓度为40mg/L，5FU浓度为10mg/L，卡培他滨浓度为200mg/L。电场处理期间同时给药治疗。
图8实验结果表明，与单独使用奥沙利铂或5FU或卡培他滨相比，电 场和奥沙利铂或5FU或卡培他滨联合使用显著差异性降低了结肠癌细胞活力。与单独使用5FU相比，电场联合5FU后使细胞活力从67.78％降低到了28.71％；与单独使用卡培他滨相比，电场联合卡培他滨后使细胞活力从70.29％降低到了53.12％；与单独使用奥沙利铂相比，电场联合奥沙利铂后使细胞活力从45.73％降低到了24.10％。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准，说明书及附图可以用于解释权利要求的内容。

Claims (12)

  1. 一种结肠癌治疗系统，所述系统包括：
    患者信息处理模块以及输出模块；
    所述样本信息处理模块用于接收采用药物治疗的结肠癌患者信息，所述信息至少包括所述结肠癌患者接受所述药物的用药信息；所述药物选自铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种；
    所述输出模块用于接收所述患者信息处理模块输出的信息，并指导对所述结肠癌患者的肿瘤电场治疗。
  2. 根据权利要求1所述的结肠癌治疗系统，所述肿瘤电场治疗所用电场为交变电场。
  3. 根据权利要求2所述的结肠癌治疗系统，所述输出模块用于调整所述交变电场的频率为150kHz～250kHz。
  4. 根据权利要求2所述的结肠癌治疗系统，所述输出模块用于调整所述交变电场的场强≥1.5Vpeak/cm。
  5. 根据权利要求4所述的结肠癌治疗系统，所述输出模块用于调整所述交变电场的场强为≥2.2Vpeak/cm。
  6. 根据权利要求2所述的结肠癌治疗系统，所述输出模块用于调整所述交变电场的干预时间≥48h。
  7. 根据权利要求6所述的结肠癌治疗系统，所述输出模块用于调整所述交变电场的干预时间≥72h。
  8. 根据权利要求1～7任一项所述的结肠癌治疗系统，所述铂基化疗药物选自铂、顺铂、卡铂、奈达铂、奥沙利铂、沙铂、四硝酸三铂中的一种或多种。
  9. 根据权利要求1～7任一项所述的结肠癌治疗系统，所述用药信息包括所述药物的种类、给药方式、给药起止时间、用药后的副作用中的一种 或多种。
  10. 铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种在制备结肠癌药物中的应用；
    所述结肠癌药物的受试者为经过肿瘤电场治疗的结肠癌患者。
  11. 一种用于结肠癌治疗的交变电场发生装置，其包括电极，当所述电极作用于受试者时，能够对所述受试者的肿瘤细胞施加交变电场，所述交变电场的频率为150kHz～250kHz，场强≥1.5Vpeak/cm，交变电场的干预时间≥48h；所述受试者为结肠癌患者且经过铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种药物治疗。
  12. 一种治疗受试者中的结肠癌的方法，所述方法包括：将铂基化疗药物、5-氟脲嘧啶和卡培他滨中的一种或多种施用给受试者；和将交变电场施加于受试者的靶区域；
    所述铂基化疗药物优选自铂、顺铂、卡铂、奈达铂、奥沙利铂、沙铂、四硝酸三铂中的一种或多种；
    所述交变电场优选的频率为150kHz～250kHz；
    所述交变电场优选的场强≥1.5Vpeak/cm；
    所述交变电场优选的干预时间≥48h。
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