Methylthioadenosine phosphorylase, (MTAP) is a key enzyme in the adenine and methionine salvage pathways. MTAP is encoded on human chromosome 9p21 in close proximity to the p16INK4a and p14ARF tumor suppressor genes a...Methylthioadenosine phosphorylase, (MTAP) is a key enzyme in the adenine and methionine salvage pathways. MTAP is encoded on human chromosome 9p21 in close proximity to the p16INK4a and p14ARF tumor suppressor genes and is frequently co-deleted with p16INK4a in many cancers. Deletion of MTAP has been reported to create a reliance of MTAP–/– tumors on de novo purine synthesis to maintain adequate pools of AMP, leading to increased sensitivity to purine synthesis inhibitors, such as L-alanosine. The ‘Achilles heel’ created by the loss of MTAP in cancer cells provides a unique therapeutic opportunity whereby MTAP–/– tumors could be selectively targeted with purine synthesis inhibitors and normal tissues could be preferentially rescued with MTAP substrates, such as MTA. We demonstrate that, in contrast to published literature, MTAP–/– cells are not more sensitive to inhibition of de novo purine synthesis than MTAP+/+ cells. Although MTA can preferentially rescue MTAP+/+ cells from purine-synthesis inhibitor toxicity in vitro, MTA protects cells of both genotypes from L-alanosine equivalently in vivo. Our data demonstrate that in vivo, adenine salvaged from plasma and adjacent tissues is sufficient to protect MTAP–/– tumors from the effects of purine synthesis inhibitors. These results suggest targeting MTAP–/– tumors with de novo purine synthesis inhibitors is unlikely to provide significant benefit over other therapeutic strategies and may explain, at least in part, the lack of efficacy of L-alanosine in clinical trials.展开更多
Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose,especially on small biopsy specimens.There are updated guidelines on the diagnosis and classification of mesothelioma...Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose,especially on small biopsy specimens.There are updated guidelines on the diagnosis and classification of mesothelioma,which incorporate advancements in understanding mesothelioma biology published in the literature over recent years.This review will discuss marked developments and/or improvements that have been made,including:(1)to the histologic classifications of mesothelioma;(2)the use of such classifications and nuclear grading in prognosis;(3)the indispensability of ancillary studies in the diagnosis of mesothelioma;(4)the application of these pleural based classifications and diagnostic schemes in peritoneal mesothelioma;and(5)the potential for diagnosis of mesothelioma in situ.展开更多
文摘Methylthioadenosine phosphorylase, (MTAP) is a key enzyme in the adenine and methionine salvage pathways. MTAP is encoded on human chromosome 9p21 in close proximity to the p16INK4a and p14ARF tumor suppressor genes and is frequently co-deleted with p16INK4a in many cancers. Deletion of MTAP has been reported to create a reliance of MTAP–/– tumors on de novo purine synthesis to maintain adequate pools of AMP, leading to increased sensitivity to purine synthesis inhibitors, such as L-alanosine. The ‘Achilles heel’ created by the loss of MTAP in cancer cells provides a unique therapeutic opportunity whereby MTAP–/– tumors could be selectively targeted with purine synthesis inhibitors and normal tissues could be preferentially rescued with MTAP substrates, such as MTA. We demonstrate that, in contrast to published literature, MTAP–/– cells are not more sensitive to inhibition of de novo purine synthesis than MTAP+/+ cells. Although MTA can preferentially rescue MTAP+/+ cells from purine-synthesis inhibitor toxicity in vitro, MTA protects cells of both genotypes from L-alanosine equivalently in vivo. Our data demonstrate that in vivo, adenine salvaged from plasma and adjacent tissues is sufficient to protect MTAP–/– tumors from the effects of purine synthesis inhibitors. These results suggest targeting MTAP–/– tumors with de novo purine synthesis inhibitors is unlikely to provide significant benefit over other therapeutic strategies and may explain, at least in part, the lack of efficacy of L-alanosine in clinical trials.
文摘Mesothelioma is a rare malignant tumor of the serosal membranes that can be challenging to diagnose,especially on small biopsy specimens.There are updated guidelines on the diagnosis and classification of mesothelioma,which incorporate advancements in understanding mesothelioma biology published in the literature over recent years.This review will discuss marked developments and/or improvements that have been made,including:(1)to the histologic classifications of mesothelioma;(2)the use of such classifications and nuclear grading in prognosis;(3)the indispensability of ancillary studies in the diagnosis of mesothelioma;(4)the application of these pleural based classifications and diagnostic schemes in peritoneal mesothelioma;and(5)the potential for diagnosis of mesothelioma in situ.
