Gopal M, Shahabuddin M S
Department of Studies & Research in Biochemistry, Kuvempu University, Davanagere, Karnataka, India.
Indian J Med Res. 2004 May;119(5):198-205.
BACKGROUND & OBJECTIVES: The compounds containing novel tetracyclic condensed quinoline ring system is of interest because of its close relationship with anticancer drug ellipticine. 8-Methoxypyrimido[4(1),5(1):4,5]thieno(2,3-b)quinoline-4(3H)-one (MPTQ) was investigated to study its effect on in vitro growth inhibition and clonogenic cell survival assay on three tumour cell lines, human promyelocytic leukemia HL-60, melanoma B16F10 and neuro 2a. A systematic study was carried out to evaluate its antitumour efficacy against B16 murine melanoma. Antiinflammatory and analgesic activities of MPTQ were also studied.
The cytotoxicity of MPTQ on HL-60, B16F10 and neuro 2a cells was estimated by trypan blue exclusion test. The antitumour activity was evaluated using single dose, multiple/daily injections (days 3-6) or intermittent treatments over two weeks against s.c. implanted B16melanoma, both in terms of increased life span and tumour growth inhibition. Antiinflammatory activity was seen on carrageenan induced hind paw oedema. Counting the number of abdominal constrictions after the injection of acetic acid assessed the analgesic response.
MPTQ is cytotoxic to all the cell lines tested and ID50 being in the range of 0.08-1.0 microM. MPTQ was studied for anticancer activity in the clonogenic assay. Drug was applied over a wide dose range by 24 h exposure, yielding clear dose-response effects. In vivo antitumour efficacy against B16 melanoma showed evidence of major antitumour activity for MPTQ. Single and multiple i.p. doses of drug proved high level activity against the s.c. grafted B16melanoma, significantly increasing survival (P<0.001) and inhibiting tumour growth (T/C of 3.0%). A reduction (76.48%) in paw volume was noted in 40 mg/kg dose of which was comparable to antiinflammatory activity of 150 mg/kg i.p. of phenylbutazone. Analgesic activity was found to be of peripheral type as there was reduction of 74 per cent in writhing response by MPTQ in dose of 40 mg/kg in mice.
INTERPRETATION & CONCLUSION: The results suggested that the compounds containing pyrimidothienoquinoline system particularly 8-methoxy derivative might be potentially useful antitumour agent. We conclude that the correlation of physicochemical properties of the new series of pyrimidothienoquinolines with their pharmacological properties, might help in trying to understand the mechanism of pyrimidothienoquinolines series.
含有新型四环稠合喹啉环系统的化合物因其与抗癌药物椭圆玫瑰树碱密切相关而备受关注。对8-甲氧基嘧啶并[4(1),5(1):4,5]噻吩并(2,3 - b)喹啉-4(3H)-酮（MPTQ）进行了研究，以探讨其对人早幼粒细胞白血病HL - 60、黑色素瘤B16F10和神经母细胞瘤2a这三种肿瘤细胞系的体外生长抑制作用及克隆形成细胞存活试验的影响。开展了一项系统研究以评估其对B16小鼠黑色素瘤的抗肿瘤疗效。还研究了MPTQ的抗炎和镇痛活性。
通过台盼蓝排斥试验评估MPTQ对HL - 60、B16F10和神经母细胞瘤2a细胞的细胞毒性。使用单次剂量、多次/每日注射（第3 - 6天）或两周内的间歇治疗，通过皮下接种B16黑色素瘤来评估抗肿瘤活性，包括延长生存期和抑制肿瘤生长。观察角叉菜胶诱导的后爪水肿来评估抗炎活性。注射醋酸后计数腹部收缩次数来评估镇痛反应。
MPTQ对所有测试的细胞系均具有细胞毒性，半数抑制浓度（ID50）在0.08 - 1.0微摩尔范围内。在克隆形成试验中研究了MPTQ的抗癌活性。通过24小时暴露在广泛的剂量范围内应用药物，产生了明显的剂量反应效应。对B16黑色素瘤的体内抗肿瘤疗效显示MPTQ具有主要的抗肿瘤活性。单次和多次腹腔注射药物对皮下移植的B16黑色素瘤显示出高水平活性，显著提高了生存率（P<0.001）并抑制了肿瘤生长（肿瘤生长抑制率为3.0%）。40毫克/千克剂量时观察到爪体积减少（76.48%），这与15毫克/千克腹腔注射苯基丁氮酮的抗炎活性相当。发现镇痛活性为外周型，因为40毫克/千克剂量的MPTQ使小鼠扭体反应减少了74%。
结果表明，含有嘧啶并噻吩喹啉系统的化合物，特别是8 - 甲氧基衍生物可能是潜在有用的抗肿瘤药物。我们得出结论，新系列嘧啶并噻吩喹啉的物理化学性质与其药理性质之间的相关性，可能有助于尝试理解嘧啶并噻吩喹啉系列的作用机制。
