METHODS FOR TREATING VIRAL DISORDERS
Disclosed are methods of treating viral disorders via the administration of an inducing agent and an anti-viral agent. In one embodiment, the inducing agent and the anti-viral agent are administered for about five days, and the anti-viral agent is subsequently administered without the inducing agent for an additional period of about sixteen days for a total cycle of about 21 days.
1 . A method for treating a viral disorder in a subject, comprising providing said subject with at least one cycle of therapy, said cycle of therapy comprising:
i) administering to the subject over a first period an inducing agent to induce expression of a viral gene product in a virus-infected cell of the subject and an anti-viral agent whose anti-viral activity is directed to the viral gene product expressed, wherein said first period of time is less than or equal to one-half of the length of the cycle, and further wherein said inducing agent and said anti-viral agent are administered in the same or separate compositions; and
ii) administering said anti-viral agent to the subject for a second period, wherein said second period is the remainder of the cycle.
2 . The method according to claim 1 , wherein said first period is less than or equal to about 5 days, and wherein said second period is at least about 5 days and less than or equal to about 16 days.
3 . The method according to claim 1 , wherein said method is a method for killing virus-infected cells in vivo.
4 . The method according to claim 1 , wherein said viral disorder is a neoplasia associated with viral infection.
5 . The method according to claim 4 , wherein said neoplasia is selected from the group consisting of lymphoma, Hodgkin disease, Burkitts lymphoma, post-transplantation lymphoproliferative disease, viral associated lymphoproliferative disease, hemophagocytic syndrome, nasopharyngeal carcinoma, gastric carcinoma, or breast cancer.
6 . The method of claim 1 , wherein the virus of the viral disorder is selected from the group consisting of Epstein-Barr virus (EBV), a herpes virus, a Kaposi's-associated human herpes virus (human herpes virus 8), a human immunodeficiency virus (HIV), a papilloma virus, a human T-cell or B-cell leukemia/lymphoma virus (HTLV), an adenovirus, or a hepatitis virus.
7 . The method of claim 1 , wherein the viral gene product is a viral enzyme, an oncogene or proto-oncogene, a transcription factor, a protease, a polymerase, a reverse transcriptase, a cell surface receptor, a structural protein, a major histocompatibility antigen, a growth factor, or a combination thereof.
8 . The method of claim 7 , wherein the viral gene product is a viral enzyme selected from a thymidine or protein kinase.
9 . The method of claim 1 , wherein the inducing agent is selected from the group consisting of a short-chain fatty acid, a short-chain fatty acid derivative, a histone deacetylase (HDAC) inhibitor, a DNA methyltransferase inhibitor, a proteasome inhibitor, a phorbol ester, an oxidized phorbol ester, ceramide, bryostatin, a cytokine, and combinations thereof.
10 . The method of claim 9 , wherein said inducing agent is selected from the group consisting of arginine butyrate, PMA (phorbol myristate acetate), TSA (trichostatin A), 2,2-dimethyl butyrate, panobinostat (LHB589), apicidin, MS-275, and largazole.
11 . The method of claim 9 , wherein said inducing agent induces viral TK expression.
12 . The method of claim 9 , wherein said inducing agent is administered at a dose of about 0.1 to about 2000 mg/kg/day or about 1 to about 100 mg/m 2 /day.
13 . The method of claim 9 , wherein said inducing agent is administered as an intravenous infusion, as a subcutaneous injection, as a solid, or as a liquid oral dosage form.
14 . The method of claim 9 , wherein said inducing agent and said anti-viral agent are administered in separate compositions.
15 . The method of claim 1 , wherein said anti-viral agent is selected from the group consisting of an interferon, an amino acid analog, a nucleoside analog, an integrase inhibitor, a protease inhibitor, a polymerase inhibitor, and a transcriptase inhibitor.
16 . The method of claim 15 , wherein the anti-viral agent is a nucleoside analog selected from the group consisting of acyclovir (ACV), ganciclovir (GCV), famcyclovir, penciclovir (PCV), foscarnet, ribavirin, zalcitabine (ddC), zidovudine (AZT), stavudine (D4T), lamivudine (3TC), didanosine (ddI), cytarabine, dideoxyadenosine, edoxudine, floxuridine, idozuridine, inosine pranobex, 2′-deoxy-5-(methylamino)uridine, trifluridine or vidarabine.
17 . A method for treating an HIV-associated disorder in a subject, comprising providing said subject with at least one cycle of therapy, said cycle of therapy comprising:
i) administering to the subject over a first period of time:
a) an anti-viral agent, and
b) an inducing agent in an amount sufficient to induce expression of a viral gene product selected from the group consisting of EBV-thymidine kinase and HIV reverse transcriptase; and
ii) continuing the administration of the anti-viral agent to the subject for the remainder of the cycle.
18 . The method of claim 17 , wherein the anti-viral agent and inducing agent of step (i) are administered in the same composition.
19 . The method of claim 17 , wherein said first period of time is less than or equal to one-half of the length of the cycle.
20 . The method of claim 19 , wherein said first period of time is less than or equal to about 5 days, and wherein said cycle is less than or equal to about 21 days.