Inhibition of human melanoma growth by prostaglandin A, D, and J analogues.
Inhibition of human melanoma growth by prostaglandin A, D, and J analogues.
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发表时间：
1986-06
期刊：
影响因子：
11.2
通讯作者：
M. D. Bregman;C. Funk;M. Fukushima
中科院分区：
文献类型：
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作者：
M. D. Bregman;C. Funk;M. Fukushima
前列腺素A（PGA）和前列腺素J2（PGJ 2）类似物相比，前列腺素A1（PGA 1）的相对抑制效力在克隆形成试验系统中测定。使用了三种人黑素瘤细胞株（C8146 A、C8146 C和C8161）、一种人黑素瘤细胞系（M1 RW 5）和一种人神经母细胞瘤细胞系（IMR-32）。在克隆形成试验系统中筛选前列腺素类似物，并利用中位效应关系通过线性回归分析剂量效应曲线。计算机生成的50%和95%抑制剂量表明，15-脱氧-16-羟基-16-乙烯基-前列腺素A2（DHV-PGA 2）在抑制人黑素瘤细胞的克隆形成生长方面的活性比PGA 1高出2至3倍。基于50%的抑制剂量，PGJ 2及其类似物的效力是PGA 1的2至5倍。δ 12-和δ 12，14-PGJ 2是测试的最有效的野牡丹素。然而，前列腺素D2（PGD 2）、PGJ 2及其类似物对神经母细胞瘤的95%抑制剂量与PGA 1相比未显示出任何活性增强，表明这些类似物活性中的某些肿瘤特异性可能由神经母细胞瘤数据表示。还测试了在11位含有氟化物取代的前列腺素的活性。正如我们先前用环戊烷环中不含α，β-不饱和羰基的其它类似物观察到的，9 β，15 α-二羟基-11 β-氟前列腺-5-顺式-13-反式-二烯酸和9 α，15 α-二羟基-11 β-氟前列腺-5-顺式-13-反式-二烯酸不抑制人黑素瘤细胞的克隆形成生长。皮下给药对在无胸腺裸鼠中生长的已建立的人黑素瘤肿瘤引起显著的生长抑制。治疗时间表范围为1至8天。皮下注射40 mg/kg/天剂量的PGA 1导致肿瘤生长抑制20%。较高剂量（100和200 mg/kg/天）使肿瘤生长减少80%。较高剂量与可逆毒性、腹泻和皮肤炎症相关。以20 mg/kg/天的剂量施用DHV-PGA 2导致肿瘤生长减少40%。DHV-PGA 2的体内效力增加对应于在克隆形成测定系统中获得的结果。
The relative inhibitory potency of prostaglandin A (PGA) and prostaglandin J2 (PGJ2) analogues compared to prostaglandin A1 (PGA1) was determined in a clonogenic assay system. Three human melanoma cell strains (C8146A, C8146C, and C8161), a human melanoma cell line (M1RW5) and a human neuroblastoma cell line (IMR-32) were used. Prostaglandin analogues were screened in the clonogenic assay system and the dose effect curves were analyzed by linear regression utilizing the median effect relationship. The computer-generated 50% and 95% inhibitory doses showed that 15-deoxy-16-hydroxyl-16-vinyl-prostaglandin A2 (DHV-PGA2) was from two- to three-fold more active than PGA1 in inhibiting the clonogenic growth of human melanoma cells. Based on the 50% inhibitory dose, PGJ2 and its analogues were from two to five times more potent than PGA1. The delta 12- and delta 12,14-PGJ2 were the most potent of the prostaglandins tested. However, the 95% inhibitory dose for prostaglandin D2 (PGD2), PGJ2 and its analogues against neuroblastoma did not show any enhancement in activity in comparison to PGA1, suggesting that some tumor specificity in the activity of these analogues may be signified by the neuroblastoma data. Prostaglandins which contained a fluoride substitution at position 11 were also tested for activity. As we previously observed with other analogues which did not contain an alpha, beta-unsaturated carbonyl group in the cyclopentane ring, 9 beta, 15 alpha-dihydroxy-11 beta-fluoroprosta-5-cis-13-trans-dienoic acid and 9 alpha, 15 alpha-dihydroxy-11 beta-fluoroprosta-5-cis-13-trans-dienoic acid did not inhibit the clonogenic growth of human melanoma cells. Administration s.c. to established human melanoma tumors growing in athymic nude mice caused a significant growth inhibition. The treatment schedules ranged from 1 to 8 days. Injection s.c. of PGA1 at a dose of 40 mg/kg/day resulted in a 20% suppression in tumor growth. Higher doses (100 and 200 mg/kg/day) effected an 80% reduction in tumor growth. The higher doses were associated with reversible toxicities, diarrhea and skin inflammation. Administration of DHV-PGA2 at a dose of 20 mg/kg/day resulted in 40% reduction in tumor growth. The increased in vivo potency of DHV-PGA2 corresponds to the results obtained in the clonogenic assay system.