Dacarbazine-induced immunogenicity of a murine leukemia is attenuated in cells transfected with mutated K-ras gene.
Strong immunogenicity is induced by antitumor triazene compounds in tumor cells through a mutagenic mechanism. A highly immunogenic <<D>> clone, isolated from a dacarbazine-treated L5178Y leukemia of DBA/2 mice, was transfected with K-ras mutated at codon 12 (i.e. ras(m12)). This transfected clone presents at least 2 mutations, one concerning K-ras gene, and the other affecting an unrelated gene, responsible for the generation of a highly immunogenic, MHC class I restricted non-self peptide. The results indicate that cells of <<D>> clone transfected with ras(m12) were less immunogenic than cells of the same origin transfected with the vector alone. Moreover, ras(m12)-transfected cells showed lower levels of H-2K(d) gene expression with respect to those detectable in control cells. In addition, in vivo and in vitro sensitization against <<D>> clone carrying mutated ras did not result in a strong cytotoxic T lymphocyte response against ras(m12)-transfected non immunogenic L5178y target cells. These preliminary results suggest that K-ras mutation could down-regulate the level of tumor immunogenicity, possibly acquired through a mutagenic process affecting other unrelated genes.
Testorelli
C
C
Dept. of Pharmacology, Chemotherapy and Toxicology, School of Medicine, State University of Milan, Italy.
Bussini
S
S
De Filippi
R
R
Marelli
O
O
Orlando
L
L
Greiner
J W
JW
Grohmann
U
U
Tentori
L
L
Giuliani
A
A
Bonmassar
E
E
Graziani
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003606:Dacarbazine / Q000494:pharmacology*; D011905:Genes, ras / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis; D007940:Leukemia L5178 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D014162:Transfection / Q000235:genetics
D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D003606:Dacarbazine