Effect of liposomally trapped antitumour drugs on a drug-resistant mouse lymphoma in vivo.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001085:Arabinofuranosylcytosine Triphosphate / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D008081:Liposomes / Q000008:administration & dosage*; D008223:Lymphoma / Q000188:drug therapy*; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental / Q000188:drug therapy
D000970:Antineoplastic Agents; D008081:Liposomes; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D008727:Methotrexate