Takemoto M, Kuroda M, Urano M, Nishimura Y, Kawasaki S, Kato H, Okumura Y, Akaki S, Kanazawa S, Asaumi J, Joja I, Hiraki Y
Department of Radiology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Int J Hyperthermia. 2003 Mar-Apr;19(2):193-203. doi: 10.1080/0265673021000035235.
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 degrees 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 degrees 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 degrees 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.
业已表明，热疗可增强某些化疗药物的细胞毒性。然而，高温下最有效的药物（或药物组合）尚未确定。先前的一项研究表明，高温下的首选药物可能与生理温度下的不同，而且烷化剂在高温下可能最为有效。为进一步探究这些可能性，对化疗药物的效果进行了比较。这些药物包括环磷酰胺、异环磷酰胺、美法仑、顺二氯二氨铂（II）、5-氟尿嘧啶、丝裂霉素C和博来霉素。使用了三种肿瘤（乳腺癌、骨肉瘤和鳞状细胞癌）。将它们移植到C3H/He小鼠的足部。当肿瘤体积达到65立方毫米时，腹腔注射一种受试药物。肿瘤随即在41.5摄氏度下加热30分钟，并研究每种肿瘤的肿瘤生长（TG）时间。根据TG时间，计算出TG-50（即从65立方毫米生长至800立方毫米，接受治疗的肿瘤总数的一半所需的时间）。随后，得出肿瘤生长延迟时间（GDT）和热增强比（TER）。GDT是接受治疗的肿瘤的TG-50与未接受治疗的对照肿瘤的TG-50之差。TER是在41.5摄氏度下接受一种药物治疗的组的GDT与在室温下接受该药物治疗的组的GDT之比。结果显示，在41.5摄氏度下测试的前三种有效药物，对于每种肿瘤而言，均为烷化剂——环磷酰胺（CY）、异环磷酰胺（IFO）和美法仑（L-PAM）。顺铂的GDT小于烷化剂的GDT。观察到，对于乳腺癌使用的5-氟尿嘧啶以及对于鳞状细胞癌使用的丝裂霉素C，其TER最小，为1.1。可以得出结论，高温下烷化剂可能是多种肿瘤的首选药物。文中还讨论了与这些药物相关的热增强的可能机制。
