Richardson V J, Ryman B E
Br J Cancer. 1982 Apr;45(4):552-8. doi: 10.1038/bjc.1982.91.
A TLX-5 mouse lymphoma which was resistant to 1-β-D-arabinofuranosyl cytosine (AraC) was used in vivo to study the possibility of using liposomes as drug-delivery vehicles in order to overcome drug resistance.The effects of free drugs (AraC, AraCTP and methotrexate) and the liposomally associated drugs on the survival time of tumour-bearing mice were determined.As a more sensitive measure of cell survival, (125)IUdR was incorporated into the DNA of the ascites TLX-5 cells before i.p. injection. Cell survival and the cytotoxic effects of the drugs on the tumour cells were determined by using a double-headed gamma counter to measure the retention of the (125)I label.Both AraC and AraCTP, either as the free drugs or liposomally associated, had no effects on the tumour. Due to the lack of response of tumour cells to these drugs, further studies were initiated with free and liposomally associated methotrexate (MTX), a drug to which the cells were known to be sensitive. It was found that the liposomally associated MTX, at a 5-10-fold lower dose than the free drug, was (a) more effective in prolonging the survival of tumour-bearing mice and (b) as effective as the free drug in killing tumour cells (as measured by the (125)I retention).In vivo MTX was more effective in the liposomally associated form, whereas liposomally entrapped AraC and AraCTP were ineffective. It is proposed that in vivo liposomally associated drugs may be acting not by actively localizing in the tumour cells, but by the liposomes providing a slow-release drug depot, improving the pharmacokinetic properties of MTX.
一种对1-β-D-阿拉伯呋喃糖基胞嘧啶（AraC）耐药的TLX-5小鼠淋巴瘤在体内用于研究使用脂质体作为药物递送载体以克服耐药性的可能性。测定了游离药物（AraC、AraCTP和甲氨蝶呤）以及与脂质体结合的药物对荷瘤小鼠存活时间的影响。作为细胞存活更敏感的指标，在腹腔注射前将（125）IUdR掺入腹水TLX-5细胞的DNA中。通过使用双头γ计数器测量（125）I标记的保留情况来确定细胞存活以及药物对肿瘤细胞的细胞毒性作用。AraC和AraCTP无论是游离药物形式还是与脂质体结合的形式，对肿瘤均无作用。由于肿瘤细胞对这些药物无反应，因此对游离的和与脂质体结合的甲氨蝶呤（MTX，已知细胞对该药物敏感）展开了进一步研究。结果发现，与脂质体结合的MTX，剂量比游离药物低5至10倍时，（a）在延长荷瘤小鼠存活时间方面更有效，（b）在杀死肿瘤细胞方面与游离药物效果相同（通过（125）I保留情况衡量）。在体内，与脂质体结合的MTX更有效，而脂质体包裹的AraC和AraCTP则无效。有人提出，在体内与脂质体结合的药物可能不是通过主动定位于肿瘤细胞起作用，而是通过脂质体提供缓释药物库，改善MTX的药代动力学特性。
