Discovery of a series of pyridopyrimidine derivatives as potential topoisomerase Ⅰ inhibitors

A series of new 3-benzoheterocyclic substituted pyridopyrimidines were designed and synthesized. Structures of the compounds were determined by IR, 1H NMR, and elemental analyses. The anti- proliferation activity of 13 novel compounds was evaluated in A549, HL-60, BGC-823 and SMMC-7721 cell lines. Compounds 3, 5, 7, 8, 9,10 showed potent inhibitory activity against the four tested cancer cell lines. These six compounds were examined for Top I inhibition at 100 μmol/L by measuring the relaxation of supercoiled DNA in plasmid pBR322. Most of the tested compounds inhibited the enzyme at this concentration. The most potent compound 9 was as potent as camptothecin.

Therapy-related myeloid neoplasms - what have we learned so far?

Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase II inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapy-related myeloid neoplasms would help developing risk-adapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.

Effects of DNA topoisomerase IIα splice variants on acquired drug resistance

DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.