The poxvirus vaccinia virus (VV) served as the model virus for which the first antivirals, the thiosemicarbazones, were identified. This dates back to 1950; and, although there is at present no single antiviral drug specifically licensed for the chemotherapy or -prophylaxis of poxvirus infections, numerous candidate compounds have been described over the past 50 years. These compounds include interferon and inducers thereof (i.e., polyacrylic acid), 5-substituted 2'-deoxyuridines (i.e., idoxuridine), IMP dehydrogenase inhibitors, S-adenosylhomocysteine hydrolase inhibitors, acyclic nucleoside phosphonates (such as cidofovir) and alkoxyalkyl prodrugs thereof (such as CMX001), viral egress inhibitors (such as tecovirimat), and cellular kinase inhibitors (such as imatinib).
Bromovinyldeoxyuridine (BVDU) is a highly potent and selective antiherpetic agent which offers great potential for the treatment of severe herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) infections in cancer patients. BVDU inhibits the replication of HSV-1 and VZV at a concentration as low as 1-10 ng/ml; and the proliferation of tumor cells transformed with the HSV-1 thymidine kinase gene is even inhibited by BVDU concentrations lower than 1 ng/ml. Moreover, BVDU is inhibitory to Epstein-Barr virus replication in vitro at a concentration of 0.02 micrograms/ml. Due to the action of pyrimidine nucleoside phosphorylases, BVDU is rapidly degraded to the free pyrimidine base bromovinyluracil (BVU). In contrast to BVDU, which is cleared from the bloodstream within 2-3 hours, BVU persists in the plasma for at least 24 hours. During this period BVU can be converted again to BVDU upon administration of deoxythymidine, deoxyuridine or any other deoxyribonucleoside capable of transferring its deoxyribosyl moiety onto BVU. BVU owes its long persistence in the bloodstream to the fact that it does not act as substrate for dihydrothymine dehydrogenase, the enzyme that catalyzes the first step in the catabolic pathway of pyrimidines. On the contrary, BVU acts as an efficient inhibitor of this enzyme and thereby prevents the degradation of fluorouracil (FU), a well-known anticancer agent. As a consequence, BVDU via BVU enhances the antitumor activity of FU, as has been demonstrated in the murine P388 leukemia model. Thus, BVDU may be useful in anticancer chemotherapy from several viewpoints, e.g. for treatment of intercurrent herpesvirus infections, and, in combination with FU, for treatment of those malignant diseases that are amenable to FU therapy.
(E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU) was examined for its ability to increase the survival rate of mice infected intracerebrally with herpes simplex virus type 1 (strain KOS). BVDU was administered orally (through the drinking water), intraperitoneally, or subcutaneously at doses ranging from 40 to 400 mg/kg per day, starting 0, 2, 4, or 6 days postinfection. Regardless of the route of administration, BVDU effected a significant reduction in the mortality rate of mice infected with herpes simplex virus type 1 if treatment was initiated shortly after virus infection, i.e., day 0 or 2 (or day 4, if BVDU was administered subcutaneously) postinfection, at a dosage of 80 mg/kg per day or higher. Similar beneficial effects were noted with orally administered BVDU in mice inoculated intraperitoneally or intranasally with herpes simplex virus type 1. These findings establish the therapeutic efficacy of BVDU in the systemic treatment of herpes simplex virus type 1 encephalitis in mice.
The effect of the antiviral agent (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine (cidofovir) on the EBV-associated tumor nasopharyngeal carcinoma (NPC) was evaluated in NPC xenografts in athymic mice. Intratumoral injection arrested tumor growth within 1 week, and by 4 weeks, tumors regressed to 8-75% (39 +/- 33%) of the original size, whereas control tumors injected with PBS grew to 282 +/- 25% of the original size. Ganciclovir slowed but did not arrest or cause regression of tumor growth. A striking antitumor effect was also produced by systemic administration; at 4 weeks, tumors were 79 +/- 49% of the original size, compared with 635 +/- 91% for the controls. Widespread apoptosis was detected after treatment for 2-6 days in C15 as well as two other NPC xenografts, C17 and C18; the latter NPCs have mutations in the p53 gene. These data indicate that cidofovir induces rapid cell death through apoptosis in EBV-transformed epithelial cells.
The antiviral activity of the double-stranded complex poly(rI) . poly(rC) in cell culture was restored or even surpassed if the constituent homopolymers were administered separately. Poly(rI) primed the cells for the antiviral activity of poly(rC) and poly(rC) primed for poly(rI), but neither poly(rI) nor poly(rC) primed the cells for the antiviral activity of noncomplementary homopolynucleotides. The priming effect of poly(rI) was significantly reduced if the poly(rI)-primed cells were treated with either T(1) ribonuclease or diethylaminoethyl (DEAE)-dextran before addition of poly(rC), and the priming effect of poly(rC) was significantly reduced if the poly(rC)-primed cells were treated with either pancreatic ribonuclease or DEAE-dextran before addition of poly(rI). (3)H-labeled poly(rC) bound more rapidly to poly(rI)-treated cells than to control cells. Cell-associated poly(rC) was markedly more resistant to pancreatic ribonuclease treatment if the cells had been incubated with poly(rI) before exposure to poly(rC). Our results clearly indicate that poly(rI) and poly(rC) added successively to cell cultures do not act independently but reunite at the cellular level, most likely at the outer cell membrane.
The efficacy of oral brivudin vs. intravenous acyclovir was compared in a randomized multicentered study under double-blind conditions using the double-dummy technique. Forty-eight patients with a herpes zoster rash less than 72 hours in duration were entered in the study. Brivudin was given as one 125-mg tablet every 6 hours. Acyclovir was infused over 1 hour at a dose of 10 mg/kg every 8 hours. Treatment was continued for 5 days. There was no significant difference between the treatment groups when analyzed in terms of new lesion formation, increase in the area of rash within the primary dermatome, cutaneous dissemination, and affection of mucous membranes or visceral organs. Both treatment regimes were also equally effective in the time to full crusting of lesions. Oral brivudin and intravenous acyclovir were well tolerated by most patients. There was no need to interrupt the treatment in any case. As effective as intravenous acyclovir in the treatment of herpes zoster, oral brivudin offers the potential for outpatient treatment of herpes zoster in immunocompromised patients.
