thioguanine-anhydrous and 5--methylthioadenosine

Castrate-resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2, and ARF genes. It is rare for this deletion to occur in primary prostate tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient-derived neuroendocrine xenograft growth while protecting the host from 6-thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology.

Topics: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 9; Cyclin-Dependent Kinase Inhibitor p16; Deoxyadenosines; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neuroendocrine Tumors; Prostatic Neoplasms; Purine-Nucleoside Phosphorylase; Sequence Analysis, DNA; Thioguanine; Thionucleosides; Treatment Outcome; Urethral Neoplasms; Xenograft Model Antitumor Assays

Chicken splenic cells, stimulated by concanavalin A, secreted a factor or factors into the culture medium which supported the survival of neurons from sympathetic ganglia of chick embryos. The effect of this conditioned medium (CM) was similar to the effect of nerve growth factor (NGF). However, the enhanced survival effect of CM was unaffected by K-252a, a protein kinase inhibitor which completely abolished the effect of NGF. 6-Thioguanine, an inhibitor of NGF-activated protein kinase N, blocked the survival effects of both NGF and CM on sympathetic neurons, but a dose required for the half-maximal inhibition for the survival effect of CM was 10 times higher than that for NGF. H-7, an inhibitor of protein kinase C, did not block the effect of either CM or NGF. On the other hand, the survival effect of both CM and NGF was blocked to the same extent by 5'-deoxy-5'-methylthioadenosine and LiCl. These results suggest that activated splenic cells secreted neuronal survival-promoting factor(s) into CM and that the cellular mechanisms promoting neuronal survival by CM are different from those promoting neuronal survival induced by NGF.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adenosine; Animals; Cell Survival; Cells, Cultured; Chickens; Culture Media; Deoxyadenosines; Ganglia, Sympathetic; Isoquinolines; Kinetics; Lymphocyte Activation; Lymphocytes; Nerve Growth Factors; Neurons; Piperazines; Proadifen; Protein Kinase Inhibitors; Spleen; Thioguanine; Thionucleosides