Modulation of multidrug resistance by verapamil or mdr1 anti-sense oligodeoxynucleotide does not change the high susceptibility to lymphokine-activated killers in mdr-resistant human carcinoma (LoVo) line

Two sublines were derived from the colon adenocarcinoma line LoVo, the first one was sensitive (LoVo/H) and the second one was made resistant to doxorubicin (LoVo/Dx). When tested for susceptibility to lysis by different types of immune effectors, LoVo/Dx appeared more sensitive than LoVo/H to the killing of CD3⁺CD5⁺CD16^-, CD3^-CD16⁺-enriched lymphokine activated killers (LAK) or activated macrophages. In order to check whether this effect was due to different expression of glycoprotein P170 between the two LoVo sublines (30% vs. 90% of positive cells), a pharmacological and genetic modulation of P170 was carried out in LoVo cells. Treatment of LoVo/Dx with the calcium channel blocker verapamil (VRP), strongly impaired P170 function as evaluated by reduced Dx resistance, without affecting the lysability of LoVo/Dx cells by LAKs. Moreover, the significant inhibition of P170 expression resulting from the treatment of LoVo/Dx with mdrI anti-sense olideoxynucleotide also failed to change the high lysability of LoVo/Dx by LAKs. These results, therefore, indicate that molecules other than P170 are involved in the increased lysis of LoVo/Dx subline by immune effectors and that down-regulation of the P170 expression or function will not reduce the potential effectiveness of cancer chemo-immunotherapy.