nitrophenols and Thymus-Neoplasms

The tumour suppressor p53 transcriptionally regulates a range of target genes that control cell growth and survival. Mutations of p53 have been implicated in the development of approximately 50% of human cancers, including those instigated by exposure to mutagens. Although numerically rare, cancers can arise as a consequence of inherited mutations, such as in the Li-Fraumeni syndrome, which is caused by mutation of one p53 allele. Gene-targeted mice deficient for p53 have been generated to study this familial cancer syndrome. On a C57BL/6 background, p53-deficient mice develop primarily thymic lymphoma and more rarely sarcoma. Evasion of apoptosis is considered to be essential for neoplastic transformation. As proteins of the Bcl-2 family are the critical regulators of apoptosis, we investigated the role of the pro-survival members Bcl-2, Bcl-x(L) and Bcl-w in cancer development in p53(+/-) and p53(-/-) mice by testing whether ABT-737, a pharmacological inhibitor of these proteins, could prevent or delay tumourigenesis. Our studies showed that ABT-737 prophylaxis only caused a minor delay and reduction in γ-radiation-induced thymic lymphoma development in p53(-/-) mice, but this was accompanied by a concomitant increase in sarcoma. These data show that, collectively, Bcl-2, Bcl-x(L) and Bcl-w have only minor roles in thymic lymphoma development elicited by defects in p53, and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process.

Topics: Alleles; Animals; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Biomimetic Materials; Biphenyl Compounds; Humans; Lymphoma; Mice; Mice, Knockout; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms, Radiation-Induced; Neoplastic Syndromes, Hereditary; Nitrophenols; Piperazines; Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thymus Neoplasms; Tumor Suppressor Protein p53

The (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific T suppressor cell hybridoma 7C3-13 was established by fusing splenic B10.BR T cells enriched on NP-coated petri dishes with the AKR thymoma BW5147. 7C3-13 was selected by anti-NPb idiotypic and anti-I-Jk antibodies in microcytotoxicity tests. The hybridoma expressed H-2k, I-Jk, Qa-1, Thy-1.1 as well as idiotypic (binding site-related) and framework Ig VH determinants, while it was negative for I-A, I-E/C, Thy-1.2, Lyt-1, Lyt-2 and Ig constant region determinants. Hapten-binding receptor material could be isolated from 7C3-13 cells on NP-coupled nylon nets and functionally active T suppressor factor (TsF) could be extracted from the hybridoma. Both types of soluble molecules express NPb idiotype, but the TsF carries I-J determinants in addition while the isolated receptors do not. The molecular weight of the isolated receptor material is 80 000, that of the TsF activity is 27 000 and 57 000-64 000, respectively. We thus were able to show that NP-binding molecules can be obtained in the form of cellular surface receptors, isolated receptor material and extracted TsF from one and the same, monoclonal, cell source.

Topics: Animals; Antigens, Surface; Haptens; Hybridomas; Immunoglobulin Idiotypes; Lymphokines; Mice; Molecular Weight; Nitrophenols; Phenylacetates; Receptors, Antigen, T-Cell; Suppressor Factors, Immunologic; T-Lymphocytes, Regulatory; Thymoma; Thymus Neoplasms

Topics: Alkaline Phosphatase; Animals; Kidney; Leukemia Virus, Murine; Leukemia, Radiation-Induced; Liver; Lymphoma; Male; Mice; Mice, Inbred Strains; Nitrophenols; Phosphates; Spectrophotometry; Spleen; Thymus Gland; Thymus Neoplasms