Guido Frosina

Guido Frosina
IRCCS Ospedale Policlinico San Martino, Genova, Italy · Mutagenesis & Cancer Prevention

PhD

About

103
Publications
5,150
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
3,154
Citations
Introduction
Patients with high grade gliomas (Grades III- IV) seldom recover. This is due to the infiltrative nature of these tumours and the presence of cell populations with ability to escape therapies and drive tumour recurrence and progression (Glioma Initiating Cells - GIC). Quiescence linked to constitutive activation of the DNA Damage Response (DDR) is a major mechanism of resistance in GIC and its targeting might yield significant tumour radio-sensitization and therapeutic gain.
Additional affiliations
September 2005 - present
Azienda Ospedaliera Universitaria San Martino-IST di Genova
Position
  • Improving radiotherapy of high grade gliomas
May 1988 - May 1989
Imperial Cancer Research Fund
Position
  • Transcription-coupled DNA Repair
April 1987 - present
Azienda Ospedaliera Universitaria San Martino di Genova
Position
  • DNA Repair mechanisms
Education
November 1983 - October 1986
University of Ferrara
Field of study
  • Genetics
November 1978 - October 1981
Scuola Normale Superiore
Field of study
  • Biological Sciences
November 1977 - October 1981
University of Pisa, Italy
Field of study
  • Biological Sciences

Publications

Publications (103)
Article
Ionizing radiation is a mainstay of high‐grade glioma therapy. The current standard radiotherapeutic schedule involves a total 60 Gy split in 2.0 Gy fractions delivered on weekdays for six weeks. Thereafter, almost invariably the tumor relapses and progresses. In vitro studies have demonstrated that the therapeutic effectiveness of ionizing radiati...
Article
High‐grade gliomas (HGGs; WHO grades III and IV) are invariably lethal brain tumors. Low‐dose hyper‐radiosensitivity (HRS) of HGG is a well‐established phenomenon in vitro. However, possibly linked to the unavailability of accurate animal models of the diseases, this therapeutic effect could not be consistently translated to the animal setting, thu...
Article
Full-text available
Albeit the effort to develop targeted therapies for patients with high-grade gliomas (WHO grades III and IV) is evidenced by hundreds of current clinical trials, radiation remains one of the few effective therapeutic options for them. This review article analyzes the updates on the topic “radiotherapy of high-grade gliomas” during the period 1 Janu...
Article
Full-text available
Doxycycline (DXC) is a tetracycline antibiotic which has been proposed as a breast cancer radiosensitizer by specifically reducing the expression of the DNA repair enzyme DNA PK in breast cancer initiating cells. Since DXC presents favorable pharmacokinetics properties including the capacity to cross the blood-brain barrier, it has been hypothesize...
Article
The Ataxia Telangiectasia Mutated (ATM)-mediated DNA damage response (DDR)is a major mechanism of resistance of glioblastoma (GB)- initiating cells (GICs)to radiotherapy. The closely related Ataxia Telangiectasia and Rad3-related protein (ATR)is also involved in tumor resistance to radio- and chemotherapy. It has been shown that pharmacological inh...
Article
Full-text available
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Article
Full-text available
Purpose To investigate the radiosensitizing capacity and therapeutic efficacy of the ataxia-telangiectasia mutated (ATM) inhibitor KU60019 on orthotopic glioblastoma (GB) driven by primary glioma initiating cells (GIC) with various p53 statuses. Methods Orthotopic GB have been developed in mice by intracranial injection of different GIC lines. Fol...
Article
Full-text available
The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treat...
Preprint
The CAALA (Complex Augmentation of ALA) regimen was developed with the goal of redressing some of the weaknesses of 5-aminolevulinic acid (5-ALA) use in glioblastoma treatment as it now stands. 5-ALA is approved for use prior to glioblastoma surgery to better demarcate tumor from brain tissue. 5-ALA is also used in intraoperative photodynamic treat...
Article
Full-text available
It has been reported that the ATM kinase inhibitor KU60019 preferentially radiosensitizes orthotopic high grade gliomas (HGG) driven by established U87 and U1242 cell lines bearing specific TP53 mutations. We wished to determine whether those results could be extended to tumors driven by primary glioma initiating cells (GIC) that closely mimic clin...
Article
Full-text available
Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aime...
Article
Full-text available
Ataxia Telangiectasia and Rad3 related protein (ATR) is a central mediator of the response to DNA damage that may cause the quiescent resistance of cancer initiating cells to genotoxic radiotherapy. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that also effectively targets ATR with IC50 = 21 × 10- 9 M in cells. AZD6738 does not target significantly PI3...
Article
Full-text available
This paper outlines a treatment protocol to run alongside of standard current treatment of glioblastoma- resection, temozolomide and radiation. The epithelial to mesenchymal transition (EMT) inhibiting sextet, EIS Regimen, uses the ancillary attributes of six older medicines to impede EMT during glioblastoma. EMT is an actively motile, therapy-resi...
Article
If cancer is hard to be treated, brain cancer is even more, due to the inability of many effective drugs given systemically to cross the blood brain and blood tumour barriers and reach adequate concentrations at the tumour sites. Effective delivery of drugs to brain cancer tissues is thus a necessary, albeit not sufficient, condition to effectively...
Article
Thorough imaging is crucial for diagnosis and treatment of high-grade gliomas (HGG), lethal brain tumours with median survival ranging 1-5 years after diagnosis. Positron-emission tomography (PET) is acquiring importance in imaging of HGG since it has the formidable advantage of providing information on tumour metabolism that may be critical for co...
Article
Full-text available
High-grade gliomas [HGG (WHO grades III-IV)] are almost invariably fatal. Imaging of HGG is important for orientating diagnosis, prognosis and treatment planning and is crucial for development of novel, more effective therapies. Given the potentially unlimited number of usable tracing molecules and the elevated number of available radionuclides, PE...
Article
Unlabelled: High grade gliomas (HGGs) are fatal brain tumors due to their infiltration capacity and the presence of resistant cell populations. Further, the brain is naturally protected from many exogenous molecules by the brain blood barrier (BBB), which limits or cancels passage of cytotoxic drugs to the tumor sites. In order to cope with the la...
Article
Whilst knowledge of basic biology, diagnosis and prognosis of glioblastoma (GB - WHO grade IV) are steadily improving, advancements of therapy are discouragingly slow, with the only significant novelty during last ten years represented by introduction of temozolomide in chemotherapy. In order to analyze the current status of clinical research on GB...
Article
Genotoxic anticancer drugs explicate their effects damaging DNA, thus triggering a coordinated signal-transduction network called DNA Damage Response (DDR). Ataxia Telangiectasia Mutated (ATM) protein plays a central role in this response: activated by DNA damage, ATM phosphorylates itself and downstream effectors that arrest cell cycle allowing fo...
Article
Full-text available
We have recently reported that glioblastoma (GB) - initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (“responder” genetic profile) can be effectively and safely radio-sensitized by the ATM inhibitor KU60019. We report here on drug’s diffusion and elimination from the animal body and brain, its effects on...
Article
Full-text available
We have previously shown that pharmacological inhibition of Ataxia Telangiectasia Mutated (ATM) protein sensitizes glioblastoma-initiating cells (GIC) to ionizing radiation. Herein, we report the experimental conditions to overcome GIC radio-resistance in vitro using the specific ATM inhibitor KU-60019, two major determinants of the tumor response...
Article
Full-text available
Cigarette smoke (CS) is associated to a number of pathologies including lung cancer. Its mutagenic and carcinogenic effects are partially linked to the presence of reactive oxygen species and polycyclic aromatic hydrocarbons (PAH) inducing DNA damage. The bacterial DNA repair enzyme formamidopyrimidine DNA glycosylase (FPG) repairs both oxidized ba...
Article
Full-text available
To study novel treatments for high grade gliomas (WHO grade III and IV) we need animal models of those disorders. Orthotopic tumours in mouse or rats seem at present the most reliable in vivo glioma model in order to develop specific therapies. The orthotopic tumour characteristics should yet closely mimic the human glioma features (in particular i...
Article
Glioblastoma multiforme (WHO grade IV) is a highly lethal brain tumor. Its malignancy is in part due to cell populations refractory to radiotherapy and chemotherapy, which in some patients display stem properties (glioma stem cells-GSC). We and others have recently shown that a major mechanism of resistance of GSC to therapies resides in their slow...
Article
Previous studies have shown that tumor-driving glioma stem cells (GSC) may promote radio-resistance by constitutive activation of the DNA damage response started by the ataxia telangiectasia mutated (ATM) protein. We have investigated whether GSC may be specifically sensitized to ionizing radiation by inhibiting the DNA damage response. Two grade I...
Article
Full-text available
Oxidative damage plays a pathogenic role in various chronic degenerative diseases. Oxidative damage targeting trabecular meshwork (TM) cells as a consequence of mitochondrial damage is a pathogenic mechanism for glaucoma, the most common cause of irreversible blindness worldwide. Consequences of oxidative damage are attenuated by endocellular activ...
Article
High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of...
Article
We have previously shown that DNA repair of oxidized bases (either purines or pyrimidines) is inefficient in cells from patients with Cockayne syndrome (cs), a rare developmental and neurological genetic disorder. Here, we show for the first time that resolution of ionizing radiation (IR)-induced pH2AX foci, an indicator of DNA double-strand breaks...
Article
Patients with glioblastoma multiforme (GBM - WHO grade IV) seldom recover. This is due to the infiltrative nature of these tumours and the presence of cellular populations with ability to escape therapies and drive tumour recurrence and progression. In some cases, these resistant cells exhibit stem properties [glioma stem cells (GSC)]. This article...
Article
Full-text available
DNA repair is a double-edged sword in stem cells. It protects normal stem cells in both embryonic and adult tissues from genetic damage, thus allowing perpetuation of intact genomes into new tissues. Fast and efficient DNA repair mechanisms have evolved in normal stem and progenitor cells. Upon differentiation, a certain degree of somatic mutations...
Article
Repair of the oxidized purine 8-oxo-7,8-dihydro-2'-deoxyguanosine is inefficient in cells belonging to both complementation groups A and B of Cockayne syndrome (CS), a developmental and neurological disorder characterized by defective transcription-coupled repair. We show here that both CS-A and CS-B cells are also defective in the repair of 5-hydr...
Article
Full-text available
Although the prognosis for malignant gliomas is normally dismal, it's not infrequent in neurooncologist's experience to find cases with unusually prolonged survival. In order to understand what factors influence survival of high grade glioma patients, a cohort of 196 high (III-IV) grade glioma patients was investigated for possible association betw...
Article
Full-text available
The importance of DNA repair as a resistance mechanism in gliomas, the most aggressive form of brain tumor, is a clinically relevant topic. Recent studies show that not all cells are equally malignant in gliomas. Certain subpopulations are particularly prone to drive tumor progression and resist chemo- and radiotherapy. Those cells have been variab...
Article
Full-text available
It has been reported that cancer stem cells may contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. We have examined DNA repair in five stem and nonstem glioma cell lines. The population doubling time was significantly increased in stem compared with nons...
Article
Stem cells build and maintain organisms. Accordingly, they are particularly well-protected from damage to DNA and other cellular components. This feature becomes a serious drawback when stem cells transform and develop cancer, because they resist to radiation and chemotherapy. Various mechanisms ensure protection of stem cells. In normal stem cells...
Article
Cockayne syndrome (complementation groups A and B) is a rare autosomal recessive DNA repair disorder characterized by photosensitive skin and severely impaired physical and intellectual development. The Cockayne syndrome A and B proteins intervene in the repair of DNA modifications that block the RNA polymerase in transcribed DNA sequences (transcr...
Article
Base excision repair (BER) is the main pathway for repair of endogenous DNA damage. It was expected that different tumor types could derive from BER defects but to date this link is elusive. In vitro and molecular epidemiology studies may be used to unravel this issue.
Article
Cockayne syndrome (CS) is a rare recessive disorder characterized by a number of developmental abnormalities and premature aging. Two complementation groups (A and B) have been identified so far in CS cases. Defective transcription-coupled nucleotide excision repair is the hallmark of these patients, but in recent years evidence has been presented...
Article
Repair of the oxidized purine 8-oxo-7,8-dihydroguanine (8-oxoGua) is inefficient in cells belonging to the B complementation group of Cockayne syndrome (CS-B), a developmental and neurological disorder characterized by defective transcription-coupled repair. We show here that cells belonging to the A complementation group (CS-A) are also defective...
Article
Full-text available
Cockayne syndrome (CS) is a rare genetic disease characterized by severe growth, mental retardation and pronounced cachexia. CS is most frequently due to mutations in either of two genes, CSB and CSA. Evidence for a role of CSB protein in the repair of oxidative DNA damage has been provided recently. Here, we show that CSA is also involved in the r...
Article
Gene therapy, the treatment of disorders or pathophysiologic states on the basis of the transfer of genetic information, has been thoroughly investigated for the treatment of lung illnesses, e.g. cystic fibrosis, alpha1-antitrypsin deficiency-related emphysema and cancer. Transfer of genetic information may be further used to elevate the level of p...
Article
A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient repair mechanisms have evolved to cope with it. The major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER). In addition, an important contribution is given by O6 alk...
Article
Lying at the gas-exchange interface, lung epithelia may be at risk of oxidation-induced mutagenesis. Further, inflammation processes possibly consequent on smoking liberate reactive oxygen species that multiply the carcinogenic effects of tobacco. DNA repair mechanisms play a major role in counteracting the deleterious effects of oxidative DNA dama...
Article
Repair of some oxidized purines such as 8-oxo-7,8-dihydroguanine (8-oxoG) is inefficient in human cells in comparison to repair of other major endogenous lesions (e.g. uracil, abasic sites or oxidized pyrimidines). This is due to the poor catalytic properties of hOGG1, the major DNA glycosylase involved in 8-oxoG removal. The formamidopyrimidine DN...
Article
Full-text available
Base excision repair (BER) is the main pathway for removal of endogenous DNA damage. This repair mechanism is initiated by a specific DNA glycosylase that recognizes and removes the damaged base through N-glycosylic bond hydrolysis. The generated apurinic/apyrimidinic (AP) site can be repaired in mammalian cells by two alternative pathways which in...
Article
Full-text available
Repair of 8-oxo-7,8-dihydroguanine (8-oxoG) is inefficient in human cells due to the poor catalytic properties of hOGG1, the major DNA glycosylase involved in the removal of this oxidized base. The S3 ribosomal/repair protein from Drosophila melanogaster (dS3) is endowed with a potent 8-oxoG glycolytic activity coupled with a beta, delta-AP lyase....
Article
DNA base excision repair (BER) is the main pathway for repair of endogenous damage in human cells. It was expected that a number of degenerative diseases could derive from BER defects. On the contrary, the link between BER defects and human pathology is elusive and the literature is full of conflicting results. The fact that most studies have inves...
Article
Full-text available
Acute myelogenous leukemias (AMLs) are genetically heterogeneous and characterized by chromosomal rearrangements that produce fusion proteins with aberrant transcriptional regulatory activities. Expression of AML fusion proteins in transgenic mice increases the risk of myeloid leukemias, suggesting that they induce a preleukemic state. The underlyi...
Article
The spontaneous transformation of cultured mouse embryonic fibroblasts (MEF) from the outbred CD-1 mouse strain was investigated. Four MEF clones, obtained from four different mouse embryos, were cultured continuously for periods ranging from 300 to 400 days. MEF cells entered a "crisis" with acute loss of proliferation capacity after 16 +/- 2 days...
Article
The S3 ribosomal protein of Drosophila melanogaster possesses various DNA repair activities, including the capacity to incise at apurinic/apyrimidinic (AP) sites and 8-oxo-7,8-dihydroguanine (8-oxoG) residues. We have recently hypothesized that this multifunctional protein may improve the efficiency of DNA base excision repair (BER) in mammalian ce...
Article
8-oxo-7,8-dihydroguanine (8-oxoG) is a potent mutagenic lesion that forms at elevated levels in cellular DNA and is repaired with low efficiency in human cells. Unlike its human counterpart, the Drosophila S3 ribosomal/repair protein is endowed with a vigorous 8 oxoG repair activity that is associated to beta,delta-elimination AP lyase activity. We...
Article
Mammalian cells transfected with the S. cerevisiae APN1 protein acquire resistance to oxidizing agents, the damage of which is mainly repaired via DNA base excision repair (BER). We have recently hypothesized that this effect might be linked to the possible capacity of APN1 to accelerate mammalian BER by its 3' diesterase activity. We have investig...
Article
DNA base excision repair (BER) removes frequent DNA lesions of either endogenous or exogenous origin. Some indications point to BER defects in lung cancer patients. We have investigated the ability of ten lung cancer patients to repair natural AP sites, the most frequent genetic lesion, using an in vitro assay in which peripheral blood lymphocytes...
Article
Full-text available
DNA damage of endogenous origin may significantly contribute to human cancer. A major pathway involved in DNA repair of endogenous damage is DNA base excision repair (BER). BER is rather efficient in human cells but a certain amount of endogenous damage inevitably escapes mending and likely contributes to human carcinogenesis. Apart from some glyco...
Article
The oxidized base 8-oxo-7,8-dihydroguanine (8-oxoG), the product of deamination of cytosine uracil (U), and the sites of base loss [abasic (AP) sites] are among the most frequent mutagenic lesions formed in the human genome under physiological conditions. In human cells, the enzymatic activities initiating DNA base excision repair (BER) of 8-oxoG,...
Article
Ataxia telangiectasia (A-T) cells are sensitive to a broad range of free-radical-producing and alkylating agents. Damage caused by such agents is in part repaired by base excision [base excision repair (BER)]. Two BER pathways have been demonstrated in mammalian cells: a single-nucleotide-insertion pathway and a long-patch pathway involving resynth...
Article
Full-text available
The breast cancer predisposing genes BRCA1 and BRCA2 appear to be involved in DNA repair. In particular, the sensitivity of BRCA2-deficient mouse embryonic fibroblasts to ionizing radiation and the demonstrated interaction of the BRCA2 protein with Rad51, a major factor in recombinational repair, indicate that BRCA2 is important for double strand b...
Article
The repair of the endogenous lesion 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) was investigated in the nucleotide excision repair mutant xeroderma pigmentosum D (XPD), using human normal or transformed XPD fibroblasts and the Chinese hamster XPD cell line UV5. In vivo repair of 8-oxodG induced by hydrogen peroxide treatment and analyzed by high-perf...
Article
The repair of the endogenous lesion 8-oxo-7,8-dihydrodeoxyguanosine (8-oxodG) was investigated in the nucleotide excision repair mutant xeroderma pigmentosum D (XPB), using human normal or transformed XPD fibroblasts and the Chinese hamster XPD cell line UV5. In vivo repair of 8-oxodG induced by hydrogen peroxide treatment and analyzed by high-perf...
Article
Full-text available
The repair of the endogenous lesions 8-oxo-7,8-dihydroguanine (8-oxoG), uracil (U) and natural abasic site (AP site) was investigated using an in vitro base excision repair assay in which a plasmid substrate containing a single lesion at a defined position was repaired by mammalian cell extracts. Repair replication of an 8-oxoG/cytosine base pair p...
Article
Full-text available
The repair of the endogenous lesions 8-oxo-7,8-dihydroguanine (8-oxoG), uracil (U) and natural abasic site (AP site) was investigated using an in vitro base excision repair assay in which a plasmid substrate containing a single lesion at a defined position was repaired by mammalian cell extracts. Repair replication of an 8-oxoG/cytosine base pair p...
Article
Full-text available
A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient repair mechanisms have evolved to cope with this. The main repair pathway involved in repair of endogenous damage is DNA base excision repair. In addition, an important contribution is given by O6-alkyl...
Article
A significant contribution to human mutagenesis and carcinogenesis may come from DNA damage of endogenous, rather than exogenous, origin. Efficient repair mechanisms have evolved to cope with this. The main repair pathway involved in repair of endogenous damage is DNA base excision repair. In addition, an important contribution is given by O6-alkyl...
Article
Defective DNA repair has been suggested as a possible predisposing factor for breast cancer. We have investigated the repair of the frequent endogenous lesions abasic sites in sporadic early onset breast cancer patients and matched control individuals. No significant difference was observed between the abasic site repair capacities of peripheral bl...
Article
Defective DNA repair has been suggested as a possible predisposing factor for breast cancer. We have investigated the repair of the frequent endogenous lesions abasic sites in sporadic early onset breast cancer patients and matched control individuals. No significant difference was observed between the abasic site repair capacities of peripheral bl...
Article
Full-text available
Base excision repair (BER) is the main pathway for removal of endogenous DNA damage. This repair mechanism is initiated by a specific DNA glycosylase that recognizes and removes the damaged base through N-glycosylic bond hydrolysis. The generated apurinic/apyrimidinic (AP) site can be repaired in mammalian cells by two alternative pathways which in...
Article
DNA repair of abasic sites is accomplished in mammalian cells by two distinct base excision repair (BER) pathways: a single nucleotide insertion pathway and a proliferating cell nuclear antigen (PCNA)-dependent pathway involving a resynthesis patch of 2-10 nucleotides 3' to the lesion. The latter pathway shares some enzymatic components with the nu...
Article
Full-text available
Women in the age range 40-59 years have a >4 fold higher risk to develop cancer as compared to women in the age range birth-39 years. This age-related increase in cancer incidence might be partially linked to reduced efficiency of the DNA repair machinery. We have investigated the abasic (AP) site incision capacity of peripheral blood lymphocytes (...
Article
Full-text available
Mammalian DNA ligase III exists as two distinct isoforms denoted α and β. Both forms possess a motif that is homologous to the putative zinc finger present in poly(ADP-ribose) polymerase. Here, the role of this motif in the binding and ligation of nicked DNA and RNA substrates in vitro has been examined in both isoforms. Disruption of the putative...
Article
The human AP endonuclease (APE) activity counteracts the mutagenic and cytotoxic effects of the frequent genomic lesions abasic (AP) sites. In order to investigate the interindividual variability of APE levels, a simple and quantitative assay was developed. Crude lymphocyte extracts were incubated with a depurinated or a control supercoiled plasmid...