{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:19:40Z","timestamp":1781108380881,"version":"3.54.1"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"19","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1992,10]]},"abstract":"<jats:p>The physiologic balance between the two regulatory subunit isoforms, RI and RII, of cAMP-dependent protein kinase is disrupted in cancer cells; growth arrest and differentiation of malignant cells can be achieved when the normal ratio of these intracellular signal transducers of cAMP is restored by the use of site-selective cAMP analogs. In this study we evaluated the effects of the site-selective cAMP analog 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP) on clonogenic growth of blast progenitors from 15 patients with acute myeloblastic leukemia and 3 patients affected by advanced myelodysplastic syndrome. Leukemic blast progenitors undergo terminal divisions, giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected in a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. In all the samples tested, 8-Cl-cAMP, at micromolar concentrations (0.1-50 microM), suppressed in a dose-dependent manner both primary colony formation in methylcellulose and the recovery of clonogenic cells from suspension culture. Strikingly, in the samples from the entire group of patients, 8-Cl-cAMP was more effective in inhibiting the self-renewing clonogenic cells than the terminally dividing blast cells (P = 0.005). In addition, in four out of six cases studied, 8-Cl-cAMP was able to induce a morphologic and\/or immunophenotypic maturation of leukemic blasts. An evident reduction of RI levels in fresh leukemic cells after exposure to 8-Cl-cAMP was also detected. Our results showing that 8-Cl-cAMP is a powerful inhibitor of clonogenic growth of leukemic blast progenitors by primarily suppressing their self-renewal capacity indicate that this site-selective cAMP analog represents a promising biological agent for acute myeloblastic leukemia therapy in humans.<\/jats:p>","DOI":"10.1073\/pnas.89.19.8884","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T08:09:52Z","timestamp":1149062992000},"page":"8884-8888","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":19,"title":["Inhibition of the self-renewal capacity of blast progenitors from acute myeloblastic leukemia patients by site-selective 8-chloroadenosine 3',5'-cyclic monophosphate."],"prefix":"10.1073","volume":"89","author":[{"given":"A","family":"Pinto","sequence":"first","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Aldinucci","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Gattei","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Zagonel","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Tortora","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Budillon","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y S","family":"Cho-Chung","sequence":"additional","affiliation":[{"name":"Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1992,10]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.89.19.8884","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T13:30:25Z","timestamp":1649856625000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.89.19.8884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1992,10]]},"references-count":0,"journal-issue":{"issue":"19","published-print":{"date-parts":[[1992,10]]}},"alternative-id":["10.1073\/pnas.89.19.8884"],"URL":"https:\/\/doi.org\/10.1073\/pnas.89.19.8884","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1992,10]]},"assertion":[{"value":"1992-10-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}