September 28-30, 1989)
. Spanning the entire process of malignant transformation and tumor progression, reports by 22 researchers from both countries focused on genes and enzymes involved in the bioactivation of carcinogens; structural DNA modifications caused by oxygen radicals and DNA-reactive molecular species contained in food pyrolysates; DNA repair in relation to mutagenesis and carcinogenesis; signal transduction and gene expression in tumor promotion; molecular mechanisms in fos gene-induced transformation; carcinogen-specific and cell-type-selective point mutations and chromosome alterations; reversion of the malignant state in fibroblasts transformed by activated cellular oncogenes; the use of teratocarcinomas in the study of development; oncogene effects in embryonic stem cells (ES cells), transgenic mice, and transgenic brain transplants; and cellular molecules associated with invasiveness.
Regarding the bioactivation of specific xenobiotics, current research focuses on the control of P450 gene expression, and on cell lines expressing transfected genes encoding different xenobiotics-metabolizing enzymes. Dr. Y . Fujii-Kuriyumu (Sendai) reported that 2 kinds of DNA elements are required for high expression of the P-45Oc gene in response to the inducer (methylcholanthrene): one of them, the "xenobiotics responsive element" (XRE) functions as an inducible enhancer, the other, BTE (basal transcription element), is involved in basal level expression. Regulatory factors acting on these DNA elements in rruns were identified and partially characterized, and cDNA clones for the BTE-binding factor were isolated. Dr. F . Oesch (Mainz) described the construction (from V79 Chinese hamster cells lacking cytochrome P-450 activity) of cell lines stably expressing cytochrome P450IIB 1 or cytochrome P450IA1. When cyclophosphamide (CP) and iphosphamide (IP) were tested for their cytotoxic and mutagenic effects in these cell lines, it was found that CP and IP are metabolically activated by cytochrome P450IIB1 but not by P450IA1. These and other V79-derived, genetically engineered cell lines can thus be used for identification of the respective cytochrome P450 species responsible for the bioactivation of specific xenobiotics, e.g., carcinogens and anti-cancer drugs. Dr. H. Huyutsu (Okayama) has found that hemin and chlorophyll inhibit the DNA-reactivity of compounds contained in pyrolysates of proteinous food and of other heterocyclic amines. Interestingly, hemin inhibits the bioactivation of Trp-P-2. Chlorophyll proved to be a potent inhibitor in the Drosophilu "wing-spot test" when given to larvae. The inhibitory effect seems to be due to the formation of a complex with Trp-P-2.
Dr. S. Nishirnuru (Tokyo) who first described the formation of 8-hydroxyguanosine (8-OH-dG) in the DNA of cells exposed to various agents generating free radicals, reported that 8-OH-dG in DNA often causes misreading at the position of the 8-OH-dG residue and also at a pyrimidine residue flanking this lesion. A repair enzyme specific for 8-OH-dG was partially purified from E . coli. When the second dG in codon 12 of a synthetic c-Ha-rus gene was replaced by 8-OH-dG, NIH 3T3 cells transfected with this construct were transformed to a similar extent as after transfection with a construct containing 06-methylguanine in the same