brivudine and Neoplasms

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

Progress in antiviral chemotherapy has taken place as a logical strategy for the design of antiviral agents has emerged. The second-generation nucleoside analogues, led by acyclovir, have proved their worth against herpesviruses and should now become a standard part of medical practice. Meanwhile, recombinant DNA technology has lowered the cost of interferons to the point at which the several human subtypes of these naturally occurring hormones can be subjected individually to controlled clinical trials against the viral diseases in the treatment of which they show promise. Yet, optimism about the future of antiviral chemotherapy must be tempered by the observation that most of the agents discussed in this review are described more accurately as promising rather than proven, and several of these have not yet been released in Australia at the time of writing.

Topics: Acyclovir; Amantadine; Animals; Antiviral Agents; Bromodeoxyuridine; Female; Hepatitis B; Herpes Genitalis; Herpes Simplex; Herpes Zoster; Humans; Idoxuridine; In Vitro Techniques; Interferons; Male; Neoplasms; Papillomaviridae; Respiratory Tract Infections; Ribavirin; Rimantadine; Tumor Virus Infections; Vidarabine

Topics: Acyclovir; Amantadine; Antiviral Agents; Bromodeoxyuridine; Clinical Trials as Topic; Guanine; Hepatitis B; Herpesviridae Infections; Humans; Interferons; Ketones; Neoplasms; Phosphonoacetic Acid; Vidarabine; Virus Diseases

Topics: Acyclovir; Amantadine; Antiviral Agents; Bromodeoxyuridine; Clinical Trials as Topic; Guanine; Hepatitis B; Herpesviridae Infections; Humans; Interferons; Ketones; Neoplasms; Phosphonoacetic Acid; Vidarabine; Virus Diseases

Suicide transgenes encode proteins that are either capable of activating specific prodrugs into cytotoxic antimetabolites that can trigger cancer cell apoptosis or are capable of directly inducing apoptosis. Suicide gene therapy of cancer (SGTC) involves the targeted or localized delivery of suicide transgene sequences into tumor cells by means of various gene delivery vehicles. SGTC that operates via the potentiation of small-molecule pharmacologic agents can elicit the elimination of cancer cells within a tumor beyond only those cells successfully transduced. Such "bystander effects ", typically mediated by the spread of activated cytotoxic antimetabolites from the transduced cells expressing the suicide transgene to adjacent cells in the tumor, can lead to a significant reduction of the tumor mass without the requirement of transduction of a high percentage of cells within the tumor. The spread of activated cytotoxic molecules to adjacent cells is mediated primarily by diffusion and normally involves gap junctional intercellular communications (GJIC). We have developed a novel SGTC system based on viral vector-mediated delivery of an engineered variant of human deoxycytidine kinase (dCK), which is capable of phosphorylating uridine- and thymidine-based nucleoside analogues that are not substrates for wild-type dCK, such as bromovinyl deoxyuridine (BVdU) and L-deoxythymidine (LdT). Since our dCK-based SGTC system is capable of mediating strong bystander cell killing, it holds promise for clinical translation. In this chapter, we detail the key procedures for the preparation of recombinant lentivectors for the delivery of engineered dCK, transduction of tumor cells, and evaluation of bystander cell killing effects in vitro and in vivo.

Topics: Animals; Apoptosis; Bromodeoxyuridine; Bystander Effect; Cell Line, Tumor; Deoxycytidine Kinase; Genes, Transgenic, Suicide; Genetic Therapy; HEK293 Cells; Humans; Male; Mice; Mice, SCID; Neoplasms; Prodrugs; Thymidine

Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD

Topics: Amides; Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Cell Proliferation; Humans; Mice; Neoplasms; Phosphoric Acids

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

The thymidine analogue (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdUrd), which is an antiviral agent effective against herpes simplex virus type 1 and varicella zoster virus, has also proved to be a potent inhibitor of dihydrouracil dehydrogenase, the major degrading enzyme of the anticancer drug fluorouracil (FUra). To evaluate the effect of BVdUrd on the pharmacokinetics of FUra in cancer patients, BVdUrd was administered orally at a daily dose of 250 mg (five patients) or 3 x 250 mg (five patients). FUra was infused at doses of 110-400 mg over 10 min. Blood and urine samples were collected regularly during a period of up to 50 h. BVdUrd was rapidly absorbed, peak plasma levels of 0.6-7.1 micrograms/ml being achieved after 1-2 h. Following a rapid decline, plasma BVdUrd levels remained higher than 10 ng/ml for up to 2 days after BVdUrd administration. The total body clearance of FUra was approximately 61/h and t1/2 markedly increased to 4-7 h. The mean urinary excretion of FUra was 50%. No differences in FUra kinetics were observed between patients receiving one or three oral doses of BVdUrd. We conclude that the concomitant use and subsequent interaction of FUra and the antiviral agent BVdUrd resulted in an impressive inhibition of FUra breakdown and marked increase of renal clearance. The findings indicate that the simultaneous use of FUra and drugs resembling this antiviral agent in patients may result in unexpected toxicity. Further experience with BVdUrd and new analogues might enable the development of new FUra treatment schedules and treatment designs e.g. combinations with leucovorin.

Topics: Adult; Aged; Antiviral Agents; Bromodeoxyuridine; Female; Fluorouracil; Humans; Male; Middle Aged; Neoplasms

BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine] has proved effective in the treatment of varicella-zoster virus diseases in patients with malignancies. In 13 out of 20 patients a prompt cessation of new vesicle formation accompanied by rapid resolution of fever, crusting and complete epithelialisation of cutaneous lesions were noted. Only in few cases a prolonged recovery from the severe zoster occurred. When starting the treatment later than 48 hours after the onset of initial rash the dissemination of epithelial lesions could not be prevented. BVDU was well tolerated. Laboratory abnormalities were observed only in some cases and did not result in interruption of treatment.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Bromodeoxyuridine; Female; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Neoplasms; Opportunistic Infections

In the period June 1980-April 1983, 21 children with malignant disease were admitted because of an intercurrent varicella or zoster infection. They were treated with the new antiviral drug BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine]. The drug was administered orally at a dose of 15 mg/kg per day for 5 days. All our patients responded promptly to BVDU treatment and recovered completely from their varicella or zoster infections without complications. No toxic side-effects due to the drug were observed.

Topics: Administration, Oral; Adolescent; Animals; Antiviral Agents; Bromodeoxyuridine; Chickenpox; Child; Child, Preschool; Female; Herpes Zoster; Humans; Male; Neoplasms

BVDU [(E)-5-(2-bromovinyl)-2'-deoxyuridine] is a highly potent and selective anti-herpes drug. It is particularly active against Varicella zoster virus, as demonstrated in cell culture and animals (monkeys). BVDU has been administered orally, at a dose of 7.5 mg/kg/day for 5 days, to 20 patients with severe localised or disseminated Herpes zoster. All patients had a malignant disorder for which they had been given intensive chemo- or radiotherapy. Upon BVDU treatment a rapid cessation of the acute Herpes zoster episode was noted in all but one patient. In the majority of patients progression of the infection was arrested within 1 day of starting treatment. No toxic side-effects could be attributed to the drug at the dosage used.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antiviral Agents; Bromodeoxyuridine; Drug Evaluation; Female; Fever; Herpes Zoster; Humans; Male; Middle Aged; Neoplasms; Time Factors

Topics: Antiviral Agents; Bromodeoxyuridine; Herpes Zoster; Humans; Neoplasms