Horsman M R, Siemann D W, Chaplin D J, Overgaard J
Department of Experimental Clinical Oncology, Danish Cancer Society, Aarhus University Hospital, Aarhus C.
Radiother Oncol. 1997 Nov;45(2):167-74. doi: 10.1016/s0167-8140(97)00127-8.
Nicotinamide is a radiation sensitizer currently undergoing clinical testing. This was an experimental study to determine the importance of drug dose and time interval between drug administration and irradiation for radiosensitization.
Nicotinamide (50-500 mg/kg) was injected intraperitoneally into CDFI or C3H mice and drug plasma pharmacokinetics were determined by HPLC. Radiosensitization was measured in tumours and normal tissues after local irradiation. The tumours were a C3H mammary carcinoma, the KHT sarcoma and the SCCVII carcinoma. Tumour response was assessed using either growth delay (C3H) or clonogenic survival (KHT/SCCVII). Normal tissue toxicities evaluated included early responding skin (development of moist desquamation of the foot) and late responding bladder (reservoir function estimated by cystometry) and lung (ventilation rate measured by plethysmography).
All nicotinamide peak plasma concentrations were seen within 30 min after injection. Irradiating tumours at peak times resulted in enhancement ratios (ERs) of 1.27 (C3H), 1.75 (KHT) and 1.45 (SCCVII) with high nicotinamide doses and 1.27 (C3H), 1.28 (KHT) and 1.36 (SCCVII) after giving clinically relevant doses (100-200 mg/kg). Lower ERs were observed when the time interval between drug injection and irradiation was increased beyond the peak time. Irradiating normal tissues at peak times after injecting 100-200 mg/kg nicotinamide gave ERs of 1.20 (skin), 0.90 (bladder) and 1.02 (lung).
Clinically achievable doses of nicotinamide will enhance tumour radiation damage while having minimal effects in normal tissues, but for the best tumour effect radiation should be given at the time of peak plasma drug concentrations.
烟酰胺是一种目前正在进行临床试验的放射增敏剂。这是一项实验研究，旨在确定药物剂量以及给药与照射之间的时间间隔对放射增敏作用的重要性。
将烟酰胺（50 - 500 mg/kg）腹腔注射到CDFI或C3H小鼠体内，通过高效液相色谱法测定药物血浆药代动力学。在局部照射后，测量肿瘤和正常组织中的放射增敏作用。肿瘤包括C3H乳腺癌、KHT肉瘤和SCCVII癌。使用生长延迟（C3H）或克隆形成存活（KHT/SCCVII）评估肿瘤反应。评估的正常组织毒性包括早期反应的皮肤（足部湿性脱屑的发展情况）、晚期反应的膀胱（通过膀胱测压法评估储尿功能）和肺（通过体积描记法测量通气率）。
注射后30分钟内可见所有烟酰胺血浆峰值浓度。在峰值时间照射肿瘤，高剂量烟酰胺时的增强比（ER）分别为1.27（C3H）、1.75（KHT）和1.45（SCCVII），给予临床相关剂量（100 - 200 mg/kg）后分别为1.27（C3H）、1.28（KHT）和1.36（SCCVII）。当药物注射与照射之间的时间间隔超过峰值时间时，观察到较低的ER。注射100 - 200 mg/kg烟酰胺后在峰值时间照射正常组织，ER分别为1.20（皮肤）、0.90（膀胱）和1.02（肺）。
临床上可达到的烟酰胺剂量将增强肿瘤辐射损伤，同时对正常组织影响最小，但为获得最佳肿瘤效果，应在血浆药物浓度峰值时进行照射。
