piperidines and Papilloma

RAS-driven malignancies remain a major therapeutic challenge. The two-stage 7,12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) model of mouse skin carcinogenesis has been used to study mechanisms of epithelial tumor development by oncogenic Hras. We used mice with an Hras(G12V) knock-in allele to elucidate the early events after Hras activation, and to evaluate the therapeutic effectiveness of farnesyltransferase inhibition (FTI). Treatment of Caggs-Cre/FR-Hras(G12V) mice with TPA alone was sufficient to trigger papilloma development with a shorter latency and an ∼10-fold greater tumor burden than DMBA/TPA-treated WT-controls. Hras(G12V) allele copy number was increased in all papillomas induced by TPA. DMBA/TPA treatment of Hras(G12V) knock-in mice induced an even greater incidence of papillomas, which either harbored Hras(G12V) amplification or developed an Hras(Q61L) mutation in the second allele. Laser-capture microdissection of normal skin, hyperplastic skin and papillomas showed that amplification occurred only at the papilloma stage. HRAS-mutant allelic imbalance was also observed in human cancer cell lines, consistent with a requirement for augmented oncogenic HRAS signaling for tumor development. The FTI SCH66336 blocks HRAS farnesylation and delocalizes it from the plasma membrane. NRAS and KRAS are not affected as they are alternatively prenylated. When tested in lines harboring HRAS, NRAS or KRAS mutations, SCH66336 delocalized, inhibited signaling and preferentially inhibited growth only of HRAS-mutant lines. Treatment with SCH66336 also induced near-complete regression of papillomas of TPA-treated Hras(G12V) knock-in mice. These data suggest that farnesyl transferase inhibitors should be reevaluated as targeted agents for human HRAS-driven cancers, such as those of bladder, thyroid and other epithelial lineages.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Line, Tumor; Enzyme Inhibitors; Farnesyltranstransferase; Gene Dosage; Gene Knock-In Techniques; Genes, ras; Humans; Mice, Mutant Strains; Mutation; Papilloma; Piperidines; Pyridines; Skin Neoplasms; Tetradecanoylphorbol Acetate

Three chlorinated nitrosopiperidines, 3-chloro-, 4-chloro-, and 3,4-dichloronitrosopiperidine, were administered to groups of 20 male Fischer 344 rats at a concentration of 0.17 mM in drinking water. Treatment with the monochloro compounds lasted for 30 weeks, while treatment with the dichloro compound lasted for 21 weeks. Almost all of the animals died with esophageal tumors. There was also a significant incidence of tumors of the forestomach and tongue in the rats treated with the monochloro compounds. Using the rate of death of the animals with tumors as an index, the relative potency of the three compounds increases from 3-chloro- to 4-chloro- to 3,4-dichloronitrosopiperidine.

Topics: Animals; Carcinogens; Carcinoma; Drinking; Esophageal Neoplasms; Male; Nitrosamines; Papilloma; Piperidines; Rats; Stomach Neoplasms; Time Factors; Tongue Neoplasms

A total of 320 Chinese hamsters (Cricetulus griseus) (CH) were subcutaneously (s.c.) treated with 1/5, 1/10, or 1/20 LD50 of N-nitrosomorpholine (NM) or N-nitrosopiperidine (NP). In the CH, NM and NP both produced up to a 100% rate of papillomas of the cheek pouch, tongue, pharynx, esophagus and forestomach. Occasionally squamous cell carcinomas also developed in these organs. A high rate of hepatomas was realized by NP.

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cricetinae; Esophageal Neoplasms; Female; Liver Neoplasms; Male; Morpholines; Mouth Neoplasms; Neoplasms, Experimental; Nitrosamines; Nitroso Compounds; Nose Neoplasms; Papilloma; Pharyngeal Neoplasms; Piperidines; Respiratory Tract Neoplasms; Stomach Neoplasms

Topics: Acid Phosphatase; Adenocarcinoma; Alkaline Phosphatase; Animals; Carcinoma; Carcinoma, Papillary; Carcinoma, Squamous Cell; Cell Division; Cell Transformation, Neoplastic; Hyperplasia; Injections, Subcutaneous; Male; Nasal Mucosa; Neoplasms, Experimental; Nitroso Compounds; Nose Neoplasms; Papilloma; Piperidines; Rats; Thymidine; Tritium

Topics: Administration, Oral; Animals; Body Weight; Carcinogens; Esophageal Neoplasms; Esophagus; Hyperplasia; Liver; Liver Neoplasms; Male; Microscopy, Electron; Neoplasms, Experimental; Nitroso Compounds; Organ Size; Papilloma; Piperidines; Rats

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Esophageal Neoplasms; Hemangioendothelioma; Liver Neoplasms; Lung Neoplasms; Male; Mice; Neoplasms, Experimental; Nitroso Compounds; Papilloma; Piperidines; Stomach Neoplasms

Topics: Amino Alcohols; Animals; Carcinogens; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esters; Ethylamines; Ethylenediamines; Gastrointestinal Neoplasms; Neoplasms, Experimental; Nitrosamines; Nitroso Compounds; Papilloma; Piperazines; Piperidines; Precancerous Conditions; Rats; Sarcosine; Stomach Neoplasms; Time Factors; Tongue Neoplasms; Urethane