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 verpamil (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 mdr1 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.
Rivoltini
L
L
Division of Experimental Oncology D, Istituto Nazionale Tumori, Milan, Italy.
Colombo
M P
MP
Supino
R
R
Ballinari
D
D
Tsuruo
T
T
Parmiani
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000230:Adenocarcinoma / Q000188:drug therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004317:Doxorubicin; D004351:Drug Resistance; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects*; D008264:Macrophages; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D004317:Doxorubicin; D014700:Verapamil