Human polyomaviruses and cancer: an overview

The name of the family Polyomaviridae, derives from the early observation that cells infected with murine polyomavirus induced multiple (poly) tumors (omas) in immunocompromised mice. Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models. The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T (tumor) antigens. Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation, immune evasion and downregulation of apoptosis. The first two human polyomaviruses were isolated over 45 years ago. However, recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples. Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals, particularly in organ transplant recipients. This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients. Four polyomaviruses namely, Merkel cell polyomavirus (MCPyV), Trichodysplasia spinulosa polyomavirus (TSPyV), John Cunningham Polyomavirus (JCPyV) and BK polyomavirus (BKPyV) have been associated with the development of specific malignant tumors. However, present evidence only supports the role of MCPyV as a carcinogen to humans. In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV, TSPyV, JCPyV and BKPyV in human cancers.

Human papillomavirus and genome instability: from productive infection to cancer

Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.

Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients

BACKGROUND: Usual treatment regimens with vancomycin often fail to provide adequate serum levels in patients with severe infections. METHODS: Retrospective analysis of vancomycin trough serum measurements. The following parameters were calculated by Bayesian analysis: vancomycin clearance, distribution volume, and peak estimated concentrations. The area under the concentration curve (AUC) (total daily dose/24 h clearance of vancomycin) was used to determine the effectiveness of treatment through the ratio of AUC/minimum inhibitory concentration (MIC) above 400, using MIC = 1 µg/mL, based on isolates of Staphylococci in cultures. RESULTS: Sixty-one vancomycin trough measurements were analyzed in 31 patients. AUC/MIC > 400 was obtained in 34 out of 61 dosages (55.7%), but the mean vancomycin dose required to achieve these levels was 81 mg/kg/day. In cases where the usual doses were administered (40-60 mg/kg/day), AUC/MIC > 400 was obtained in nine out of 18 dosages (50%), in 13 patients. Trough serum concentrations above 15 mg/L presented a positive predictive value of 100% and a negative predictive value of 71% for AUC/MIC > 400. CONCLUSION: Higher than usual vancomycin doses may be required to treat staphylococcal infections in children with oncologic/hematologic diseases. Since the best known predictor of efficacy is the AUC/MIC ratio, serum trough concentrations must be analyzed in conjunction with MICs of prevalent Staphylococci and pharmacokinetic tools such as Bayesian analysis.

[Effect of ionizing radiation of cobalt 60 on radiosensitivity of HeLa cells infected with Measles virus]

Radiotherapy is one of the cancer treatment methods. Prescribed dose for each fraction is considered based on radiosensitivity of tumoral and normal tissues. Viral agents are the effective factors on tissue sensitivity. This research aimed to determine the effect of ionizing radiation of Cobal 60 on radiosensitivity of Hela cells infected with Measles virus. In this study, the radiosensitivity of Hela cells is investigated experimentally and qualitively. The cells have been cultivated in two groups [experimental and blank] and plating efficiency has been obtained. Then 100 lambda measles virus with serial dilution method was used to induce infection in different ratio for experimental group. After cell growth and passage, the two groups were irradiated with 2Gy gamma radiation of cobalt 60. Results respectively indicated cell death increases up to 5-7%, 15-20% and 50-65%, after 2Gy irradiation by Co 60 for contaminating to Measles in low, moderate and high concentrations. The result in radiotherapy of cancers showed, in prescribing dose fraction non cancer disease should be considered

Cytomegalovirus infection among childre with blood malignancies

To correlate the virologic and serologic study results of cytomegalovirus [CMV] with the clinical syndromes among children with hematological malignancies seen at King Abdulaziz University Hospital [KAUH] in Jeddah, Saudi Arabia. A total of 49 children were studied. The patients were 27 children suffering from different hematological malignancies. Twenty two children were admitted to the study as controls. Human foreskin fibroblast [HFF] cell culture was used for virus isolation. Immunofluorescence assay [IFA] using monoclonal antibodies [abs] to CMV was performed on all infected cultures. Antibodies [IgM and IgA] to CMV in the sera were detected by an enzyme-linked immunosorbant assay [ELISA] and a Latex Agglutination test [IgG]. All patients showed seropositivity for anti CMV-IgG. Eighteen patients [67%] with positive anti-CMV IgG showed no evidence of active infection or excretion of CMV. Nine patients [33%] showed seropositivity, 2 of them [22%] with exertion of CMV in the urine but with no evidence of active infection, and the other 7 [78%] patients developed active CMV infection presented by excretion of CMV from one or more body sites, elevated or non elevated serum anti-CMV IgG and with or without the presence of anti-CMV IgM. Out of these 9 patients 2 had evidence of primary infection and the remaining 7 patients had latent CMV reactivation episode. The presence of anti-CMV IgA had no relation neither to the excretion of CMV, nor to the elevated anti-CMV IgG and to positive anti-CMV IgM. There was no CMV active infection in the control subjects evidenced by the absence of excretion of CMV in the samples, and negative anti-CMV IgM in the serum despite the detection of anti-CMV IgG which indicated past exposure to CMV early in childhood

Molecular genetic approach to cell proliferation control and neoplasia

A number of gene products involved in the control of cell proliferation fall into one of two classes: oncogenes and tumor suppressor genes. The same gene products have also been associated with malignant growth (tumors) caused by radiation, chemicals and tumor viruses. Here we describe our attempts to elucidate the molecular mechanisms underlying polyomavirus-induced cell transformation and the anti-tumor activity of glucocorticoid hormones. Wild type and mutant polyomavirus middle T (MT) overexpressing cell lines, generated with retroviral vector constructs, were used to investigate the role played by peptide growth factor primary response genes (fos, jun, myc, JE, KC) in viral transformation and to map the transduction pathway of the mitogenic signal of MT. Overexpression of MT leads to increased AP-1 (Fos/Jun) transcriptional complex activity. Transformation defective mutant analysis allowed the identification of sites in the MT molecule that are crucial for this activity. Two different approaches were used to investigate the molecular basis for glucocorticoids anti-tumor activity, namely: blind cloning of cDNAs and analysis of growth control genes in C6 glioma cell variants that are either hypersensitive (C6/ST1) or unresponsive to glucocorticoids (C6/P7). Four different glucocorticoid-regulated cDNA sequences were isolated using differential hybridization. A number of differentially expressed sequences were isolated from glucocorticoid-treated C6/ST1 cells by differential display (DDRT-PCR) and are currently being characterized. Expression of known growth control genes in C6/ST1 cells allowed the identification of important candidates for glucocorticoid hormone targets.