Small cell lung cancer (SCLC) is a common human cancer clearly distinguished from non-small cell lung cancer (NSCLC) by a marked deficiency of HLA-A,B,C and B2-microglobulin (B2m) mRNA transcription. This deficiency can be largely reversed by incubation of SCLC cells with interferon. The decrease in HLA antigens may have profound implications on the host response to tumor cells and may partly explain the rapid local growth and early metastases of SCLC tumors compared to NSCLC. The proposed study will examine the most likely mechanisms underlying the regulation of these genes using cultured cancer cell lines and human HLA and B2m cDNA probes. As interferon has been shown to induce the expression of HLA-A,B,C, and B2m antigens in SCLC cells, it will be used in each set of experiments to determine its effect on each mechanism of gene regulation tested. The chromatin configuration and degree of methylation in sequences flanking HLA-A,B,C and B2m genes will be studied using specific restriction endonucleases and DNase I. Suppressor proteins specifically inhibiting transcription of class I major histocompatibility complex mRNA will be looked for in SCLC cells. As there is strong circumstantial evidence linking c-myc amplification and HLA deficiency in SCLC, a direct causal relationship between the c-myc gene product and the HLA transcription block will be formally investigated. RNA blotting experiments will determine whether interferon can turn off c-myc transcription in SCLC cells. Some of the experiments will involve transfection of isolated histocompatibility and c-myc genes in SCLC and NSCLC cells and study of their subsequent regulation within the host cells. These genes will be co-transfected with the selectable bacterial enzyme xanthine-guanine phosphoribosyltransferse carried by the vector Ecogpt. Other experiments are designed to examine the intermediary molecules involved in the induction of class I MHC genes by interferon. The personnel and laboratory facilities of the University of Maryland Cancer Center are well equipped to undertake this project and such basic research may lead to innovative ways of treating this malignancy.
| Marley, G M; Doyle, L A; Ordonez, J V et al. (1989) Potentiation of interferon induction of class I major histocompatibility complex antigen expression by human tumor necrosis factor in small cell lung cancer cell lines. Cancer Res 49:6232-6 |
| Doyle, L A; Giangiulo, D; Hussain, A et al. (1989) Differentiation of human variant small cell lung cancer cell lines to a classic morphology by retinoic acid. Cancer Res 49:6745-51 |
| Doyle, L A; Cuttitta, F; Mulshine, J L et al. (1987) Markedly different antibody responses to immunized small cell and non-small cell lung cancer cells. Cancer Res 47:5009-13 |
