ABSTRACT
We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity.
Subject(s)
Apoptosis/drug effects , Apoptosis/physiology , Dihydrotestosterone/pharmacology , Etoposide/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins/physiology , Base Sequence , Cell Survival/drug effects , Drug Interactions , Humans , Immunohistochemistry , Male , Molecular Sequence Data , Oligonucleotides, Antisense/pharmacology , Proto-Oncogene Proteins/analysis , Proto-Oncogene Proteins/biosynthesis , Proto-Oncogene Proteins c-bcl-2 , Tumor Cells, CulturedABSTRACT
Eighty-five prostate cancer specimens from prostate resections were analyzed for the presence of p53 gene mutations by immunohistochemical staining for P53 protein. DNA from thirty-four of these samples was also analyzed for mutations in exons 5-8 by single-strand chain polymorphism (SSCP) analysis. One sample had P53 staining by immunohistochemistry, one sample was positive for a p53 mutation by SSCP, and one sample was positive by both techniques. Mutations in the two samples that were positive by SSCP were confirmed by nucleotide sequencing. In a separate study of ten lymph nodes that contained prostate cancer metastases, one had detectable P53 protein by immunohistochemical staining. Therefore, p53 mutations appear to be low frequency events in primary prostate cancer.
Subject(s)
Genes, p53/genetics , Mutation , Prostatic Neoplasms/genetics , Proto-Oncogenes/genetics , Aged , Aged, 80 and over , Base Sequence , DNA, Neoplasm/analysis , DNA, Single-Stranded , Humans , Male , Middle Aged , Molecular Sequence Data , Polymorphism, Restriction Fragment Length , Prostatic Neoplasms/chemistry , Tumor Suppressor Protein p53/analysisABSTRACT
Synthetic subunit vaccines to sporozoites, merozoites, and gametes are being developed for malaria. The vaccine strategy assumes that the population to be immunized will respond favorably to these vaccine antigens. Using sera of 35 adults and 50 children from the The Gambia, West Africa, where Plasmodium falciparum is highly endemic, we examined the humoral immune response to candidate malaria vaccine antigens from sporozoites, merozoites, and gametes. We observed widespread restricted immunogenicity to defined parasite antigens in children and adults. HLA typing of adult lymphocytes demonstrated a marked diversity in HLA haplotypes in this population. Our results and those from our studies in mice suggest that genetic factors may partly explain the immunological non-responsiveness. This may necessitate re-evaluation of the malaria vaccine strategy.