A test for mutation theory of cancer: Carcinogenesis by misrepair of DNA damaged by 4-nitroquinoline 1-oxide

Abstract

Summary.-Evidence for a mutation theory of cancer is presented by reviewing the experimental work on 4-nitroquinoline 1-oxide (4NQO) carcinogenesis. 4NQO almost completely mimics u.v. light and produces 4NQO-purine adducts on DNA. When 4NQO-treated cells are held in liquid medium under appropriate conditions, the 4NQO adducts disappear from DNA, in parallel to decrease of premutational damage in Escherichia coli, or pretransformational damage in cultured mouse cells. Post-treatment with caffeine greatly diminishes the yields by 4NQO of mutants in E. coli, malignant transformants in cultured mouse cells and tumour nodules in the lung of mice. Potentially tumourigenized stem cells in the lung remain sensitive to selective killing by caffeine for at least 5 days after 4NQO treatment, in spite of their DNA being apparently replicated, an indication that carcinogen-damaged DNA in the stem cell can be transmitted to its successive daughter stem cells for many generations. This peculiar characteristic is discussed as a possible lead to the crux of the mutation theory of cancer in vivo, and a model for carcinogenesis is proposed.

Effective use of the <i>Pig-a</i> gene mutation assay for mutagenicity screening: measuring CD59-deficient red blood cells in rats treated with genotoxic chemicals

“…These results suggest that the mutagenic potential of CP is not strong, at least for genes on the X-chromosome like Piga or Hprt, and that a spontaneous Pig-a mutant frequency as low and as stable as practical may be necessary for detecting any mutagenicity induced by CP. 4-NQO forms stable quinoline monoadducts with purine bases through the enzymatic reduction of its nitro group (Kondo, 1977). A previous report described timeand dose-dependent increases of Pig-a mutant RBCs in rats treated with 4-NQO (Stankowski et al, 2011).…”

Electrophile and oxidant damage of mitochondrial DNA leading to rapid evolution of homoplasmic mutations

“…4NQO is an electrophile and a powerful carcinogen and mutagen (18). It is a UV-mimetic agent and forms charge-transfer complexes with 5Ј-deoxyribonucleotides (19,20). 4NQO forms DNA adducts and causes a wide range of DNA lesions including single-strand breaks, pyrimidine-dimer formation, abasic sites, and oxidized bases.…”

DNA Damage, Repair and Misrepair in Cancer and in Cancer Therapy

“…The modified base can also pair with thymine, and not only with cytosine . UV light (Kapetanaki et al, 2006), ionizing radiation and various chemicals (Kondo, 1977;Shrivastav et al, 2010) are examples of exogenous genotoxic agents. Some of them, such as UV light, ionizing radiation and tobacco-derived chemicals, have been firmly established, by epidemiologic, animal and in vitro studies, as carcinogens.…”

“…For instance, defects in various DNA repair pathways in hereditary diseases have been linked to the predisposition to a number of cancers (Heinen et al, 2002) (section 5). The importance of DNA repair dynamics in cancer biology became evident as early as the 1970s, when it was observed that mice treated with 4-nitroquinoline 1-oxide (4NQO), a chemical mutagen, displayed increased mortality and reduced incidence of tumors if treated with caffeine, up to five days after treatment with 4NQO (Kondo, 1977). Caffeine is now known to inhibit ATM and ATR kinases and, hence, DDR (Sarkaria et al, 1999).…”