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1.
Int J Gynecol Cancer ; 31(10): 1363-1368, 2021 10.
Article in English | MEDLINE | ID: covidwho-1370903

ABSTRACT

OBJECTIVE: COVID-19 is a global public health emergency. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological tumors. The Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) performed a survey to evaluate the impact of the COVID-19 pandemic on medical treatment of gynecological cancer, with a focus on chemotherapy and oral treatment with poly(ADP)-ribose polymerase inhibitors (PARP-i). METHODS: The survey consisted of a self-administered online questionnaire, sent via email between November 2020 and January 2021 to all members of MITO group. RESULTS: Forty-nine centers completed the questionnaire. The majority of respondents (83%) use screening tests to determine COVID-19 status in patients who were to undergo chemotherapy or oral medications. All respondents to our survey continued cancer therapy in patients who tested negative for COVID-19 during the pandemic. Seventy-three percent of respondents declared they stopped treatment with chemotherapy or PARP-i only after a positive swab and resumed therapy when negative tests were confirmed. CONCLUSIONS: COVID-19 positivity impacted patterns of treatment in patients diagnosed with ovarian cancer within the MITO group. Further investigations are needed to evaluate whether these modifications influence oncological clinical outcomes.


Subject(s)
Antineoplastic Agents/therapeutic use , COVID-19 Testing/statistics & numerical data , COVID-19/diagnosis , Genital Neoplasms, Female/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Practice Patterns, Physicians'/statistics & numerical data , Withholding Treatment/statistics & numerical data , Administration, Oral , Adult , Aged , COVID-19/complications , COVID-19/prevention & control , Female , Genital Neoplasms, Female/complications , Health Care Surveys , Health Services Accessibility/statistics & numerical data , Humans , Italy , Male , Middle Aged
2.
Curr Drug Targets ; 22(13): 1477-1484, 2021.
Article in English | MEDLINE | ID: covidwho-1048853

ABSTRACT

BACKGROUND: Activation of Poly (ADP-ribose) polymerase 1 (PARP1), a post-translational modifying enzyme, has been shown to be involved with several inflammatory and viral diseases. OBJECTIVES: The goal of this review is to highlight the mechanisms underlying PARP1 activation during viral or infectious pathogenesis and to assess potential possibilities of using PARP1 inhibitors as a therapeutic countering of SARS-CoV-2 virus. METHODS: An extensive bibliographic search was done using Pubmed, Mendeley and google scholar with key words. Pre-prints are reported with potential caveats and studies without experimental data were excluded. RESULTS: Covid-19, a global pandemic; is associated with systemic surge of inflammatory cytokines resulting in severe inflammation of the lung, heart dysfunction, ischemia, and stroke. PARP1 regulates expression of NFkB and downstream cytokine production and its inhibition is known to attenuate the expression of inflammatory cytokines. PARP1 and other PARP family members regulate viral infection, replication, and virulence. The literature clearly suggests that PARP1 plays an important role in host-pathogen interactions and pathogenesis, with pre-clinical and in vitro studies supporting the idea that PARP1 inhibition may negatively affect viability of several viruses including the replication of the SARS-CoV and SARS-CoV-2 virus. CONCLUSION: The current review discusses mechanisms of PARP1 activation during viral infection, inflammatory diseases, cytokine expression and possibility of PARP1 in regulating cytokine storm and hyper-inflammation seen with Covid-19. Additionally, in vitro studies showing the negative regulation of SARS-CoV-2 virus replication by PARP inhibitors indicates a potential therapeutic role of PARP inhibitors for Covid-19 or its variants.


Subject(s)
COVID-19/drug therapy , COVID-19/virology , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Poly(ADP-ribose) Polymerases/metabolism , SARS-CoV-2/enzymology , Animals , Cardiovascular Diseases/metabolism , Humans , Inflammation/drug therapy , Inflammation/enzymology , Lung Diseases/metabolism , Poly(ADP-ribose) Polymerases/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism
3.
Am J Respir Cell Mol Biol ; 63(5): 571-590, 2020 11.
Article in English | MEDLINE | ID: covidwho-901528

ABSTRACT

PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.


Subject(s)
Acute Lung Injury/drug therapy , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Lung/drug effects , Pneumonia, Viral/drug therapy , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Acute Lung Injury/enzymology , Acute Lung Injury/virology , Animals , Antiviral Agents/adverse effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Lung/enzymology , Lung/virology , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , SARS-CoV-2 , Signal Transduction/drug effects
4.
Br J Pharmacol ; 177(16): 3635-3645, 2020 08.
Article in English | MEDLINE | ID: covidwho-676030

ABSTRACT

Clinically approved PARP inhibitors (PARPi) have a mild adverse effect profile and are well tolerated as continuous daily oral therapy. We review the evidence that justifies the repurposing of PARPi to block the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and combat the life-threatening sequelae of coronavirus disease 2019 (COVID-19) by several mechanisms. PARPi can effectively decrease IL-6, IL-1 and TNF-α levels (key interleukins in SARS-CoV-2-induced cytokine storm) and can alleviate subsequent lung fibrosis, as demonstrated in murine experiments and clinical trials. PARPi can tune macrophages towards a tolerogenic phenotype. PARPi may also counteract SARS-CoV-2-induced and inflammation-induced cell death and support cell survival. PARPi is effective in animal models of acute respiratory distress syndrome (ARDS), asthma and ventilator-induced lung injury. PARPi may potentiate the effectiveness of tocilizumab, anakinra, sarilumab, adalimumab, canakinumab or siltuximab therapy. The evidence suggests that PARPi would benefit COVID-19 patients and trials should be undertaken.


Subject(s)
Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , COVID-19 , Coronavirus Infections/virology , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
5.
Biomed Pharmacother ; 130: 110536, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-653483

ABSTRACT

In the last three months, the whole scientific community has shifted its focus to the fight against the COVI-2 infection (COVID-19) trying to use different medications to save the patients' life. In some studies, the results were completely inconclusive, as in the case of chloroquine. However, the recent discovery on benefits deriving from use of such anticoagulants for Covid-19 patients, has increased the success of patients' treatment. Among lots of old and new drugs, PARP-inhibitors were not considered as possible option in the treatment of Covi-2 infection, being the latter able to induce the inflammatory and thrombotic cascades. Since PARP-inhibitors are able to reduce and block mechanisms leading to thrombosis and inflammation, they could be used as antithrombotic medications. Therefore, the present brief report is aimed to open the discussion on the potentials of PARP-inhibitors in non-oncological settings, like Covid-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/blood , Fibrinolytic Agents/therapeutic use , Pandemics , Pneumonia, Viral/blood , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Thrombophilia/drug therapy , Thrombosis/prevention & control , Anti-Inflammatory Agents/pharmacology , COVID-19 , Coronavirus Infections/complications , Drug Repositioning , Fibrinolytic Agents/pharmacology , Humans , Inflammation , Pneumonia, Viral/complications , Poly (ADP-Ribose) Polymerase-1/physiology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerases/physiology , SARS-CoV-2 , Thrombophilia/etiology
6.
Eur J Cancer ; 136: 99-106, 2020 09.
Article in English | MEDLINE | ID: covidwho-635276

ABSTRACT

BACKGROUND: In light of the coronavirus disease 2019 (COVID-19) pandemic, cancer centres in the United Kingdom and Europe re-organised their services at an unprecedented pace, and many patients with cancer have had their treatments severely disrupted. Patients with cancer were considered at high risk on sparse evidence, and despite a small number of emerging observational studies, the true incidence and impact of COVID-19 in the 'at-risk' population of patients with cancer is yet to be defined. METHODS: Epidemiological and clinical data were collected prospectively for patients attending the Royal Marsden Hospital and three network hospitals between March 1st and April 30th 2020 that were confirmed to have Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Significance of clinical and pathological characteristics was assessed using the Fisher's exact test and Wilcoxon rank sum test, whilst univariate and multivariate logistic regression models were used to further assess risk. The number of patients attending in March/April 2020 for face-to-face attendances was also extracted. FINDINGS: During the 2-month study period, 867 of 13,489 (6.4%) patients met the criteria leading to swab testing. Of the total at-risk population, only 113 of 13,489 (0.84%) were swab positive, 101 of 13,489 (0.75%) required hospital admission and 29 of 13,489 (0.21%) died of COVID-19. Of the patients that attended the hospital to receive cytotoxic chemotherapy alone or in combination with other therapy, 59 of 2001 (2.9%) were admitted to the hospital for COVID-19-related issues and 20 of 2001 (1%) died. Of the patients that collected targeted treatments, 16 of 1126 (1.4%) were admitted and 1 of 1126 (0.1%) died. Of the 11 patients that had received radiotherapy, 6 of 1042 (0.6%) required inpatient admission and 2 of 1042 (0.2%) died. INTERPRETATIONS: Administration of systemic anticancer therapy appears to be associated with a modest risk of severe COVID-19 infection. Based on this snapshot taken as the first wave of COVID-19 hit our practice, we conclude that continuation of active cancer treatment, even in the palliative setting, is appropriate.


Subject(s)
Antineoplastic Agents/therapeutic use , Coronavirus Infections/epidemiology , Hospitalization/statistics & numerical data , Neoplasms/epidemiology , Pneumonia, Viral/epidemiology , Radiotherapy/statistics & numerical data , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Female , Humans , Incidence , Logistic Models , Male , Middle Aged , Mortality , Multivariate Analysis , Neoplasms/therapy , Pandemics , Pneumonia, Viral/mortality , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Risk Factors , SARS-CoV-2 , United Kingdom/epidemiology , Young Adult
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