salicylates and Cell-Transformation--Neoplastic

A lipophilic farnesyl moiety attached to the carboxyl terminal cysteine of ras proteins structurally supports their membrane anchorage, required for ras-dependent growth-factor signaling and for transforming activity of ras oncoproteins. It has been shown that inhibition of ras farnesylation can block tumor growth in nude mice but that some ras-dependent tumors escape such blockage as a result of prenylation of ras. S-trans-transfarnesylthiosalicylic acid (FTS) is a potent ras-dislodging antagonist that does not affect ras prenylation but rather acts on the mature, membrane-bound ras and facilitates its degradation. Here we demonstrate that FTS induces reappearance of stress fibers in H-ras-transformed rat-1 cells (EJ cells) in vitro, inhibits their anchorage-independent growth in vitro, and blocks EJ-tumor growth in nude mice. The anchorage-independent growth of cells expressing ErbB2 (B104), but not that of v-raf-transformed cells, is also inhibited by FTS, suggesting specificity towards activated ras. FTS treatment (5 mg/kg i.p. daily) caused inhibition (75-80%) of tumor growth in nude mice implanted with EJ, but not in mice implanted with v-raf-transformed cells, with no evidence of systemic toxicity. Moreover, FTS treatment increased the survival rate of EJ-tumor-bearing mice from 48 to 68 days. Here we demonstrate anti-tumor potency in a synthetic, non-toxic, ras-dislodging antagonist acting independently of farnesyltransferases.

Topics: 3T3 Cells; Actins; Animals; Antineoplastic Agents; Cell Division; Cell Transformation, Neoplastic; Cytoskeleton; Farnesol; Genes, erbB-2; Genes, ras; Male; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Experimental; Neuroblastoma; Oncogene Proteins v-raf; Protein Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Rats; Receptor, ErbB-2; Retroviridae Proteins, Oncogenic; Salicylates; Substrate Specificity; Tumor Cells, Cultured

Currently, 25 different types of human papillomavirus (HPV) are recognized, each responsible for a characteristic clinical manifestation of warts or wart-like lesions. Increasingly, evidence supports a close relationship between certain types of HPVs--5, 8, 14, 16, 18, and perhaps 6 and 11--and malignant transformation. Before therapy is initiated, the probability of spontaneous resolution must be considered. The discomfort and possible risks of treatment must be balanced against the patient's discomfort and pain. Possible modes of treatment include topical therapy, cryotherapy and surgery, intralesional injections, and immunotherapy.

Topics: Administration, Topical; Bleomycin; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cryosurgery; Female; Humans; Immunotherapy; Injections; Male; Papillomaviridae; Salicylates; Salicylic Acid; Skin Neoplasms; Tumor Virus Infections; Uterine Neoplasms; Warts

We have studied the effects of superoxide dismutase (SOD), catalase, Cu(II) (3,5-diisopropylsalicylate)2 (CuDIPS) and other copper compounds on radiation transformation in vitro using C3H 10T1/2 cells. When present only during irradiation, high concentrations of SOD in the medium enhanced transformation, while catalase, inactivated SOD (autoclaved), CuDIPS, cupric chloride and cuprous chloride inhibited the initiation phase of radiation transformation. SOD, catalase and CuDIPS did not affect the expression phase of radiation transformation. Suppression of the TPA enhancement of transformation by catalase was a highly significant effect, while the suppression by SOD was not of statistical significance. Our results suggest that hydrogen peroxide (H2O2) may be important in the cellular damage leading to malignant transformation.

Topics: Animals; Catalase; Cell Transformation, Neoplastic; Free Radicals; Hydrogen Peroxide; Mice; Salicylates; Superoxide Dismutase; Tetradecanoylphorbol Acetate

The in vitro carcinogenic activities of 3-(N-salicyloyl)amino-1,2,4-triazole (SAT) and its two components, 3-amino-1,2,4-triazole and phenyl salicylate were examined in a transformation assay with cryopreserved hamster embryo cells. SAT induced morphological transformation at certain doses between 10 microgram/ml and 100 microgram/ml in each of 5 repeated experiments, but gave a negative result in the Salmonella mutation assay. 3-Amino-1,2,4-triazole also induced transformation in 3 repeated experiments. Phenyl salicylate did not induce transformation at any of the doses tested in 3 consecutive experiments.

Topics: Amitrole; Animals; Carcinogens; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Embryo, Mammalian; Mutagens; Salicylates; Triazoles

Several thiosemicarbazone-metal complexes inhibit the RNA dependent DNA polymerase and the transforming ability of Rous sarcoma virus. Some complexes are equally as active as the free ligand whereas the activity of others is greatly enhanced. The 2-formyl pyridine thiosemicarbazone copper (II) complex is the most potent compound of this class that we tested. Some copper complexes of salicylaldehyde derivatives are very active also, particularly N-n-butyl, N-n-hexyl and N-benzylsalicylaldimine; no nickel complex of any salicylaldehyde compound is active. In addition, other metal ligands, such as dithizone, diacetyl bis (mercaptoethylimine), N-butyl thiocarbamate, 0,0' dimethyl dithiophosphate, potassium dithiooxalate, and cis-PtII(NH3)2Cl2 were tested with varying results.

Topics: Aldehydes; Animals; Avian Sarcoma Viruses; Cell Transformation, Neoplastic; Cell Transformation, Viral; Chick Embryo; Depression, Chemical; Glyoxal; Isatin; Metals; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase; Salicylates; Structure-Activity Relationship; Sulfur; Thiosemicarbazones

Topics: Aged; Cell Transformation, Neoplastic; Female; Hodgkin Disease; Humans; Lymphoma; Polymyalgia Rheumatica; Prednisolone; Salicylates; Synovitis