Broad phase II and pharmacokinetic study of methoxy-morpholino doxorubicin (FCE 23762-MMRDX) in non-small-cell lung cancer, renal cancer and other solid tumour patients

The aim was to perform a broad phase II and pharmacokinetic study of methoxymorpholino-doxorubicin (MMRDX), a drug active against multidrug-resistant tumour cells in vitro when given by i.v. bolus at 1.5 mg m(-2) every 4 weeks, in metastatic or unresectable solid tumour patients with known intrinsic drug resistance. Patients received a maximum of six cycles. Plasma, urine and leucocyte MMRDX and its 13-dihydro metabolite pharmacokinetic analysis was performed in patients without liver metastases. Patients (n = 48, 21 NSCLC, 19 renal cell, three head and neck tumour, three cervical cancer and two adenocarcinoma of unknown primary) received 132 cycles of MMRDX. Common toxicity criteria (CTC) grade III/IV thrombocytopenia (12% of cycles) and neutropenia (27% of cycles) occurred with median nadir on day 22. Transient transaminases elevation greater than or equal to grade III/IV was observed in 7% of cycles, late and prolonged nausea greater than or equal to grade II in 34% and vomiting greater than or equal to grade II in 39%. In two patients, the left ventricular ejection fraction was reduced greater than or equal to 15%. Of 37 evaluable patients, one out of 17 NSCLC had a partial response. Mean (+/-s.d.) MMRDX AUC(0-->infinity) calculated up to 24 h after dosing was 20.4 +/- 6.2 mu g h l(-1) (n = 11) and t(1/2, gamma) was 44.2 h. Mean plasma clearance (+/-s.d.) was 37.2 +/- 7.3 l h(-1) m(-2) and volume of distribution 1982 +/- 64 l m(-2). MMRDX leucocyte levels 2 and 24 h after infusion were 450 to 600-fold higher than corresponding MMRDX plasma levels. In urine, 2% of the MMRDX dose was excreted unchanged, and 2% as metabolite. The main side-effects of 1.5 mg m(-2) every 4 weeks of MMRDX are delayed nausea and vomiting and haematological toxicity. MMRDX is characterized by extensive clearance and rapid and extensive distribution into tissues. A low response rate was observed in patients with tumours with intrinsic chemotherapy resistance

Viral strategies for circumventing p53: the case of severe acute respiratory syndrome coronavirus

International audiencePurpose of review Virtually all viruses have evolved molecular instruments to circumvent cell mechanisms that may hamper their replication, dissemination, or persistence. Among these is p53, a key gatekeeper for cell division and survival that also regulates innate immune responses. This review summarizes the strategies used by different viruses and discusses the mechanisms deployed by SARS-CoV to target p53 activities. Recent findings We propose a typology for the strategies used by different viruses to address p53 functions: hit and run (e.g. IAV, ZIKV), hide and seek (e.g. HIV1), kidnap and exploit (e.g. EBV, HSV1), dominate and suppress (e.g. HR HPV). We discuss the mechanisms by which SARS nsp3 protein targets p53 for degradation and we speculate on the significance for Covid-19 pathogenesis and risk of cancer. Summary p53 may operate as an intracellular antiviral defense mechanism. To circumvent it, SARS viruses adopt a kidnap and exploit strategy also shared by several viruses with transforming potential. This raises the question of whether SARS infections may make cells permissive to oncogenic DNA damage

Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex*

Severe acute respiratory syndrome (SARS) coronavirus is highly pathogenic in humans and evades innate immunity at multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which mobilize the front-line defense against viral infection. In this study we demonstrate that SARS coronavirus M protein inhibits gene transcription of type I interferons. M protein potently antagonizes the activation of interferon-stimulated response element-dependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKKϵ, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this element when IRF3 or IRF7 is overexpressed. M protein physically associates with RIG-I, TBK1, IKKϵ, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3·TANK·TBK1/IKKϵ complex and thereby inhibits TBK1/IKKϵ-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons