brivudine and Leukemia

Herpes viruses are among the most common and troublesome opportunistic pathogens infecting patients with neoplastic diseases. The recent development of partially effective and relatively nontoxic antiviral agents offers promise for the prophylaxis or therapy of these infections in high-risk groups. Vidarabine and acyclovir have shown efficacy in several herpes virus infections and are now licensed in the United States. Alpha interferon may also be useful in the prophylaxis or early therapy of certain herpes virus infections. Newer antiviral agents and combination therapies are under study. Early and rapid diagnosis of such infections is critical to the development of effective therapy.

Topics: Acyclovir; Antineoplastic Agents; Antiviral Agents; Bone Marrow Transplantation; Bromodeoxyuridine; Cloning, Molecular; Cytomegalovirus Infections; Herpes Simplex; Herpes Zoster; Herpesviridae Infections; Humans; Infectious Mononucleosis; Interferons; Kidney Transplantation; Leukemia; Lymphopenia; Neoplasms; Pulmonary Fibrosis; Vidarabine

Twenty-five patients with haematological diseases were treated orally with the highly potent and selective anti-herpes agent, bromovinyldeoxyuridine (BVDU), in a dosage of 7.5 mg/kg/day (divided over three or four doses a day) for 5 days for an intercurrent mucocutaneous herpesvirus infection. Of these 25 patients, 8 were severely granulocytopenic at the time of the viral infection, and 12 recently had undergone bone-marrow transplantation; 5 were under cytotoxic therapy for a lymphoproliferative disorder; 13 had herpes simplex virus type 1 (HSV-1); 1 had herpes simplex virus type 2 (HSV-2); and 11 had varicella-zoster virus (VZV) infection. In all but two patients, BVDU arrested progression of the HSV or VZV infection within 1-2 days after treatment was started. One of the two patients who failed to respond to BVDU had an HSV-2 infection. The other had an HSV-1 infection, which was highly sensitive to BVDU in vitro; BVDU may have failed in this patient because of incomplete drug intake or profuse diarrhoea, or both. The results of this preliminary uncontrolled clinical trial suggest that BVDU may be an effective and safe drug for the oral treatment of HSV-1 and VZV infections in severely immunosuppressed patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Child; Child, Preschool; Clinical Trials as Topic; Female; Herpes Simplex; Herpes Zoster; Humans; Immunosuppression Therapy; Leukemia; Lymphoma; Male; Middle Aged

Herpesvirus saimiri (HVS) has the capacity to incorporate large amounts of heterologous DNA and can infect many different human cell types. To develop its potential as a gene therapy vector, we cloned herpes simplex virus thymidine kinase (TK) gene into the HVS genome in the form of an enhanced green fluorescent protein (EGFP) fusion protein, using a cosmid-based approach. At multiplicity of infection = 100 over 90% of human leukemic K562 and Jurkat cells were transduced with HVS/EGFP-TK. Conditions of no selective pressure expression were maintained at > 92% per cell division. Expression of the EGFP-TK fusion protein rendered transfected leukaemic cells sensitive to cytotoxic treatment with the prodrugs ganciclovir (GCV) and (E)-5-(2-bromovinyl)-2'deoxyuridine (BVDU) at concentrations as low as 10 ng/ml. The viral vector was also screened against a panel of colorectal and pancreatic carcinoma cell lines. All cell lines were transduced but showed a range of sensitivity to infection. Three of the most easily transduced cell lines: Mia PaCa, HCT116 and SW948 transduced with HVS/EGFP-TK were effectively ablated by subsequent treatment with GCV or BVDU. Our results show that in its current form HVS/EGFP-TK could be utilized as an antitumour agent, or it could be developed further by inclusion of a therapeutic gene, with TK presence ensuring a mechanism of controlled removal of modified cells when no longer necessary. These results suggest that HVS/EGFP-TK has a great potential for a number of gene therapy applications.

Topics: Animals; Antiviral Agents; Aotidae; Base Sequence; Bromodeoxyuridine; Cells, Cultured; Colorectal Neoplasms; Ganciclovir; Genetic Vectors; Green Fluorescent Proteins; Humans; Jurkat Cells; K562 Cells; Kidney; Leukemia; Molecular Sequence Data; Pancreatic Neoplasms; Recombinant Fusion Proteins; Simplexvirus; Thymidine Kinase; Transfection

The anti-recombinogenic substance (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was tested for its ability to prevent adriamycin-induced mdr1 gene amplification and expression in mouse leukemia cells in vitro. F4-6 cells that were treated with stepwise enhanced doses of adriamycin acquired resistance against adriamycin. While 20 ng/ml adriamycin showed strong toxic effects in sensitive cells, the same dose was tolerated at the end of the long-term experiment following treatment with stepwise enhanced doses of adriamycin. In parallel experiments, 0.5 or 1 microg/ml BVDU was given together with adriamycin. BVDU prevented the formation of resistance against adriamycin treatment. Using differential PCR, the signal intensity of the mdr1a-specific band appeared markedly increased in adriamycin-resistant cells, while the signal intensities of the adriamycin + BVDU-treated cells resembled the intensity ratio of the untreated control cells. Beyond that, in resistant F4-6 cells increased expression of mdr genes was demonstrated by Northern blot analysis.

Topics: Animals; Antiviral Agents; Bromodeoxyuridine; DNA Repair; DNA Replication; Doxorubicin; Gene Amplification; Gene Expression Regulation, Neoplastic; Genes, MDR; Humans; Leukemia; Mice; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured

Topics: Animals; Breast Neoplasms; Bromodeoxyuridine; Humans; Isoenzymes; Leukemia; Leukocytes, Mononuclear; Thymidine Kinase