Experimental correlations of in vitro drug sensitivity with in vivo responses to ThioTEPA in a panel of murine colon tumours.
Cell lines derived from three histologically different murine colon tumours (MAC) were used to assess whether or not a tumour colony-forming assay could have retrospectively predicted the wide range of in vivo responses to the alkylating agent, ThioTEPA. Tumour responses ranged from sensitive (MAC 26) to resistant (MAC 15A), with MAC 13 showing only moderate sensitivity. In vitro chemosensitivity studies, in conjunction with pharmacokinetic data, suggest that plasma levels of the drug's primary metabolite, TEPA, should be sufficient to induce significant cell kills in all three tumour lines in vivo. Preliminary studies on the effect of pH on the cytotoxic properties of ThioTEPA in vitro have demonstrated an improved cell kill when cells were exposed to the drug under acidic conditions. As these tumours differ histologically in terms of vascularisation, tumoural pH may play an important part in determining drug efficacy and go some way towards explaining the poor in vitro/in vivo correlation in this model.
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006863:Hydrogen-Ion Concentration; D051379:Mice; D013852:Thiotepa / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D013852:Thiotepa