Modulation of telomere length in telomerase positive cells and cancer therapy

Abstract

Induction of telomere shortening, G2 arrest and apoptosis in telomerase positive cancer cells using acyclic nucleoside analogs has been disclosed. In addition, methods for impairment or prevention of tumorigenic telomerase positive cells from having a chance to grow into a tumor and methods for promoting tumor regression (decrease in size of an established tumor) using acyclic nucleoside analogs has been disclosed.

1 . An in vivo method for assessing anti-tumor efficacy of a composition or treatment of human cancer comprising telomerase positive cancer cells, the method comprising: a) providing a mouse carrying a subcutaneous xenograft of said telomerase positive cancer cells (b) subjecting the mouse to the composition or treatment, wherein the composition comprises an acyclic nucleoside analog or a pharmaceutically acceptable salt thereof and the composition reproducibly induces telomere shortening, G 2  arrest and/or massive apoptosis in said cancer cells in an vitro assay; and (c) determining that the composition or treatment is effective on the growth of the xenograft in said mouse as measured by resultant tumor-free mouse or reduced tumor volume in the mouse wherein the determining step comprises comparing the growth of the xenograft in the mouse provided in step (a) and subjected to the composition or treatment in step (b) to the growth of the xenograft in at least one other mouse as set forth in step (a) that did not receive the composition or treatment. 
     
     
         2 . The method of  claim 1 , wherein the mouse is an immunodeficient mouse. 
     
     
         3 . The method of  claim 1 , wherein the mouse is a nude mouse. 
     
     
         4 . The method of  claim 1 , wherein said cancer cells do not include cells from virus-associated cancer, wherein the method does not involve the use of non-nucleoside analog based anti-cancer agents or irradiation and wherein the composition does not contain any of nucleoside analogs selected from the group consisting of: [(S)-1-[3-hydroxy-2-(phosphomethoxy)propyl]cytosine](HPMPC), 9-(3-Hydroxy-2-phosphonyl-methoxypropyl)-adenine (HPMPA), 9-(2-[phosphonylmethoxyethyl), {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA or adefovir), 9-(2-phosphonylmethoxyethyl)guanine (PMEG), 9-[2-(phosphonomethoxy)ethyl]-2-6 diaminopurine (PMEDAP) and 9-(2-Phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPr-PMEDAP). 
     
     
         5 . The method of  claim 4 , wherein: i) the efficacy of the composition or treatment of step (b) for treating said cancer is not known, where in the said cancer is selected from the group consisting of: cervical cancer, bone cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, lung cancer, brain cancer, ovarian cancer, uterine cancer, testicular cancer, skin cancer, leukemia, melanoma, esophageal cancer, stomach cancer, colon cancer, retinal cancer and bladder cancer, and, ii) step (c) determines whether the treatment or composition is efficacious in impairing the growth of said cancer xenograft in the mouse. 
     
     
         6 . The method of  claim 4 , wherein said cancer cells are contacted with the composition in combination with a different type of nucleoside analog selected from the group consisting of: 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), and 2′,3′-didehydro-3′-deoxythymidine (d4T), wherein the different type of nucleoside analog is present in a low dose, which alone is insufficient to inhibit the growth of said cancer cells. 
     
     
         7 . The method of  claim 6 , wherein said cancer cells are selected from the group consisting of: cervical cancer cells bone cancer cells, breast cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, leukemia cells, melanoma cells, esophageal cancer cells, stomach cancer cells, colon cancer cells, retinal cancer cells and bladder cancer cells. 
     
     
         8 . The method of  claim 4 , wherein said cancer cells are cervical cancer cells or breast cancer cells. 
     
     
         9 . The method of  claim 4 , wherein said cancer cells are ovarian cancer cells. 
     
     
         10 . The method of  claim 4 , wherein said cancer cells are uterine cancer cells. 
     
     
         11 . The method of  claim 4 , wherein said acyclic nucleoside analog is selected from the group consisting of: acyclovir and penciclovir, or a prodrug thereof. 
     
     
         12 . The method of  claim 4 , wherein the different type of nucleoside analog is AZT or ddI. 
     
     
         13 . An in vivo method for assessing anti-tumor efficacy of a composition or treatment of human cancer comprising telomerase positive cancer cells, the method comprising: a) providing a mouse carrying a subcutaneous xenograft of said telomerase positive cancer cells (b) subjecting the mouse to the composition or treatment, wherein the composition comprises an acyclic nucleoside analog or a pharmaceutically acceptable salt thereof and the composition reproducibly induces telomere shortening, G 2  arrest and/or massive apoptosis in said cancer cells in an vitro assay; and (c) determining that the composition or treatment is effective on the growth of the xenograft in said mouse as measured by resultant apoptotic foci in the xenograft wherein the determining step comprises comparing the extent of apoptotic foci in the xenograft in the mouse provided in step (a) and subjected to the composition or treatment in step (b) to the extent of apoptotic foci in the xenograft in at least one other mouse as set forth in step (a) that did not receive the composition or treatment. 
     
     
         14 . The method of  claim 13 , wherein the mouse is a nude mouse. 
     
     
         15 . The method of  claim 13 , wherein said cancer cells do not include cells from virus-associated cancer, wherein the method does not involve the use of non-nucleoside analog based anti-cancer agents or irradiation and wherein the composition does not contain any of nucleoside analogs selected from the group consisting of: [(S)-1-[3-hydroxy-2-(phosphomethoxy)propyl]cytosine](HPMPC), 9-(3-Hydroxy-2-phosphonyl-methoxypropyl)-adenine (HPMPA), 9-(2-[phosphonylmethoxyethyl), {[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}phosphonic acid (PMEA or adefovir), 9-(2-phosphonylmethoxyethyl)guanine (PMEG), 9-[2-(phosphonomethoxy)ethyl]-2-6 diaminopurine (PMEDAP) and 9-(2-Phosphonylmethoxyethyl)-N6-cyclopropyl-2,6-diaminopurine (cPr-PMEDAP). 
     
     
         16 . The method of  claim 15 , wherein said acyclic nucleoside analog is selected from the group consisting of: acyclovir and penciclovir, or a prodrug thereof. 
     
     
         17 . The method of  claim 15 , wherein said cancer cells are contacted with the composition in combination with a different type of nucleoside analog selected from the group consisting of: 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI), and 2′,3′-didehydro-3′-deoxythymidine (d4T), wherein the different type of nucleoside analog is present in a low dose, which alone is insufficient to inhibit the growth of said cancer cells. 
     
     
         18 . The method of  claim 17 , wherein the different type of nucleoside analog is AZT or ddI. 
     
     
         19 . The method of  claim 17 , wherein said cancer cells are selected from the group consisting of: cervical cancer cells bone cancer cells, breast cancer cells, prostate cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, leukemia cells, melanoma cells, esophageal cancer cells, stomach cancer cells, colon cancer cells, retinal cancer cells and bladder cancer cells. 
     
     
         20 . The method of  claim 19 , wherein said cancer cells are cervical cancer cells, breast cancer cells, ovarian cancer cells or uterine cancer cells.