Methods and compositions for increasing susceptibility to radiation treatment by inhibiting suppression of numerical chromosomal instability of cancer cells

Abstract

Disclosed is a method for increasing susceptibility of cancer cells to ionizing radiation by delivering to the cells a radiosensitizing agent that has one of the following properties: (a) it perturbs the process of chromosome segregation thereby increasing chromosome missegregation; or (b) it is an inhibitor of an agent that promotes faithful chromosome segregation induces numeric chromosome instability in said cells and this instability is induced substantially simultaneously with or closely prior to or closely after irradiating the cells. Examples of such radiosensitizing agent include inhibitors of one or more of the following: Kif2b, MCAK, MPS1, Eg5/Kinesin-5 5, Polo-like kinase 4, MCAK, Bub1 and Hec1. Such agents specifically target proteins involved in maintaining or promoting faithful chromosome segregation.

What is claimed is: 
     
         1 . A method for increasing susceptibility of cancer cells to ionizing radiation comprising exposing the cancer cells to an effective amount of a radiosensitizing agent which specifically perturbs the process of chromosome segregation, inducing missegregation or specifically inhibits a second agent that promotes faithful chromosome segregation, said radiosensitizing agent thereby inducing numeric chromosome instability in said cells simultaneously with or closely prior to or closely after irradiating the cells with a therapeutically effective dose and regimen of ionizing radiation. 
     
     
         2 . The method of  claim 1  wherein the radiosensitizing agent specifically inhibits one or more of the following directly or indirectly: Kif2b, MCAK, MPS1, Eg5/Kinesin-5, Polo-like kinase 4, MCAK, NORAD, Bub1, BubR1, MAD and Hec1. 
     
     
         3 . The method of  claim 1  wherein the cancer cells are solid tumor cancer cells. 
     
     
         4 . The method of  claim 1  wherein the radiosensitizing agent is selected from the group consisting of MPS1 inhibitors, Eg5/Kinesin-5 inhibitors, Polo-like kinase 4 inhibitors, MCAK inhibitors, Bub1 inhibitors and Hec1 inhibitors. 
     
     
         5 . The method of  claim 1  wherein the ionizing radiation is administered in one or two or more divided doses. 
     
     
         6 . A method for increasing cytotoxicity of ionizing radiation in a subject to be treated for a solid malignant tumor susceptible to treatment with ionizing radiation comprising administering systemically to the subject or locally to the tumor an effective amount of an enhancer of numerical chromosome instability or an enhancer of chromosome missegregation during mitosis substantially simultaneously with or closely preceding or closely following treatment of the tumor with ionizing radiation. 
     
     
         7 . A method for reducing damage of noncancerous cells or tissue incident to ionizing radiation aimed at cancerous cells or tissue comprising exposing the noncancerous cells or tissue to an effective amount of a radioprotective agent which is an enhancer of suppression of chromosome missegregation and reduces numeric chromosome instability in said cells simultaneously with or closely prior to or closely following irradiating the cancerous cells or tissue with a therapeutically effective dose and regimen of ionizing radiation. 
     
     
         8 . The method of  claim 7  wherein the radioprotective agent is Kif2b MPS1, Eg5/Kinesin-5, Polo-like kinase 4, MCAK or NORAD.