dihydroteleocidin-b and aplysiatoxin

Topics: Alkaloids; Animals; Cell Adhesion; Cell Aggregation; Cell Transformation, Neoplastic; Enzyme Induction; Humans; Isomerism; Lactones; Lyngbya Toxins; Marine Toxins; Mice; Mollusk Venoms; Neoplasms; Ornithine Decarboxylase; Phorbols; Tetradecanoylphorbol Acetate

The evolution of a fully malignant tumor is a multistep process resulting from the action of multiple factors, both environmental and endogenous, and involves alterations in the function of multiple cellular genes. Chemical carcinogens that initiate this process appear to do so by damaging cellular DNA. In addition to producing simple point mutations, this damage appears to induce the synthesis of a trans acting factor that can induce asynchronous DNA replication. This response may result in gene amplification and/or gene rearrangement. This phenomenon may also play a role in synergistic interactions between chemicals and viruses in the causation of certain cancers. The primary target of the tumor promoters TPA, teleocidin, and aplysiatoxin appears to be the cell membrane. All three of these agents act, at least in part, by enhancing the activity of the phospholipid-dependent enzyme protein kinase C. We have proposed a stereochemical model to explain the interaction of these amphiphilic compounds with the PKC system. We have found that TPA and teleocidin markedly enhance the transformation of C3H 10T1/2 mouse fibroblasts when these cells are transfected with the cloned H-ras human bladder cancer oncogene. Thus, tumor promoters can act synergistically with an activated oncogene to enhance cell transformation. Furthermore, carcinogen-transformed rodent cells display aberrations in the expression of various endogenous retrovirus-related sequences. Activation of some of these sequences may lead to insertion mutations and further aberrations in gene expression. Thus, multistage carcinogenesis may involve both changes in cellular oncogenes and aberrations in the function of DNA sequences that control gene transcription.

Topics: Animals; Carcinogens; Cell Membrane; DNA, Neoplasm; Drug Synergism; Enzyme Activation; Gene Amplification; Gene Expression Regulation; Lyngbya Toxins; Mutagens; Oncogenes; Protein Kinase C; Structure-Activity Relationship; Tetradecanoylphorbol Acetate; Transcription, Genetic

Three potent tumor promoters of different classes, 12-O-tetradecanoylphorbol-13-acetate, dihydroteleocidin B, and aplysiatoxin, and two moderate tumor promoters, mezerein and debromoaplysiatoxin, enhanced the frequency of appearance of cadmium-resistant Chinese hamster lung cells when the cells were exposed to cytotoxic levels of CdCl2. With these compounds, the activity to induce cadmium-resistant cells correlated well with the potency of tumor-promoting activity. Cadmium resistance, which persisted after removal of the tumor promoters, was associated with the overproduction of metallothionein I messenger RNA. The amplified metallothionein I genes were shown by Southern blotting experiments. The relevance of the gene amplification caused by tumor promoters is discussed in relation to cancer development and progression.

Topics: Alkaloids; Animals; Cadmium; Carcinogens; Cell Line; Cricetinae; Cricetulus; Diterpenes; Gene Amplification; Genes; Lactones; Lung; Lyngbya Toxins; Metallothionein; Mollusk Venoms; Phorbol Esters; Terpenes; Tetradecanoylphorbol Acetate