Regulation of matrix metalloproteinase (mmp) gene expression in tumor cells via the application of electric and/or electromagnetic fields

Abstract

Methods and devices for the regulation of gene expression in tissue by applying an electric and/or electromagnetic field generated by specific and selective signals so as to treat diseases, conditions, and/or tissue. Gene expression is the up-regulation or down-regulation of the process whereby specific portions (genes) of the human genome (DNA) are transcribed into mRNA and subsequently translated into protein. Methods and devices are described for the regulation of Matrix Metalloproteinase (MMP) protein gene expression in tumor cells of various targeted tissues via the capacitive coupling or inductive coupling (e.g., by electrodes or one or more coils or other field generating devices disposed with respect to the targeted cells) of specific and selective signals to the cells of these tissues, where the resultant electric and/or electromagnetic fields treat diseased or injured tissues. The resulting methods and devices are useful for the targeted treatment and/or prevention of tumor growth and/or spread, and/or any other conditions in which MMP protein may be implicated.

1 . A method of down-regulating the gene expression of Matrix Metalloproteinase (MMP) protein in targeted tissue, comprising the steps of:
 a. generating at least one specific and selective electric signal having a frequency between 30 kHz and 120 kHz that when applied to electrodes, one or more coils, or other field generating devices operatively disposed with respect to said targeted tissue causes the generation of a specific and selective electric field having an amplitude of between 1 mV/cm and 80 mV/cm in said targeted tissue that substantially down-regulates the gene expression of MMP protein in said targeted tissue as measured by mRNA production therein; and   b. exposing said targeted tissue to the specific and selective electric field generated by said electrodes, one or more coils, or other field generating devices upon application of said at least one specific and selective electric signal thereto for a predetermined duration of time at a predetermined duty cycle from approximately 5% to 100% so as to selectively down-regulate the gene expression of MMP protein in said targeted tissue as measured by mRNA production therein.   
     
     
         2 . The method of  claim 1  wherein the generating step comprises the step of selectively varying the amplitude, duration, duty cycle, frequency, and waveform of the applied specific and selective electric signal until the gene expression of MMP protein in said targeted tissue as a result of exposure to the resultant specific and selective electric field as measured by mRNA production in the targeted tissue is substantially decreased. 
     
     
         3 . The method of  claim 1  wherein the exposing step comprises the step of exposing targeted tissue to the specific and selective electric field for a duration of between 30 minutes and 24 hours every 24 hours. 
     
     
         4 . The method of  claim 1  wherein said electric signal has a sine wave configuration. 
     
     
         5 . The method of  claim 1  wherein said generating step comprises the step of generating the specific and selective electric signal at a remote source and said exposing step comprises the step of applying the specific and selective electric field to the targeted tissue. 
     
     
         6 . The method of  claim 1  wherein the exposing step comprises the step of applying the specific and selective electric field in the targeted tissue generated by the electrodes, one or more coils, or other field generating devices upon application of said at least one specific and selective electric signal thereto to the targeted tissue through capacitive coupling or inductive coupling. 
     
     
         7 . The method of  claim 6  wherein the specific and selective electric signal applied to said electrodes causes the electrodes to generate a capacitive coupling electric field, and the specific and selective electric signal applied to said one or more coils causes said one or more coils to generate an electromagnetic field or a combined field. 
     
     
         8 . A method for treating tumors or cancerous tissue, comprising the steps of:
 a. generating at least one specific and selective electric signal having a frequency between 30 kHz and 120 kHz that when applied to electrodes, one or more coils, or other field generating devices operatively disposed with respect to targeted tissue causes the generation of a specific and selective electric field having an amplitude of between 1 mV/cm and 80 mV/cm in the targeted tissue that substantially down-regulates the gene expression of MMP protein in said targeted tissue as measured by mRNA production; and   b. exposing said targeted tissue to the specific and selective electric field generated by said electrodes, one or more coils, or other field generating devices upon application of said at least one specific and selective electric signal thereto for a predetermined duration of time at a predetermined duty cycle from approximately 5% to 100% so as to selectively down-regulate the gene expression of MMP protein in said targeted tissue as measured by mRNA production therein.   
     
     
         9 . The method of  claim 8  wherein the exposing step comprises the step of capacitively coupling or inductively coupling the specific and selective electric field to the targeted tissue. 
     
     
         10 . The method of  claim 8  wherein the exposing step comprises the step of applying/the specific and selective field to said targeted tissue as one of an electromagnetic field and a combined field. 
     
     
         11 . The method of  claim 8  wherein said electric signal has a sine wave configuration. 
     
     
         12 . The method of  claim 8  wherein the exposing step comprises the step of applying the specific and selective electric field to the targeted tissue for a duration of between 30 minutes and 24 hours at an interval of between 30 minutes and 24 hours. 
     
     
         13 . The method of  claim 8  wherein the generating step comprises the steps of starting with a starting electric signal with a signal shape and frequency that when applied to said electrodes, one or more coils, or other field generating devices generates an electric field to be generated that is known or thought to affect cellular production of MMP, performing a first dose-response curve on the amplitude of stimulation of the electric field to determine an optimal amplitude; performing a second dose-response curve on the duration of the applied electric signal using the optimal amplitude as previously found to determine an optimal duration; performing a third dose-response curve on the frequency of the applied electric signal keeping the optimal amplitude and optimal duration as previously found to determine an optimal frequency; performing a fourth dose-response curve varying the duty cycle of the applied electric signal and keeping the optimal duration, amplitude, and frequency as previously found to determine an optimal duty cycle, and keeping the optimal duration, amplitude, frequency and duty cycle constant while varying the waveform until an optimal waveform for the down-regulation of the gene expression of MMP protein as measured by mRNA production in the targeted tissue is found. 
     
     
         14 . A device for the treatment of tumors or cancerous tissue in a patient, comprising a signal source that generates at least one specific and selective signal having a frequency between 30 kHz and 120 kHz and electrodes, one or more coils, or other field generating devices connected to said signal source so as to receive said at least one specific and selective signal and that are operatively disposed with respect to targeted tissue, said electrodes, one or more coils, or other field generating devices upon receipt of said at least one specific and selective signal causing the generation of a specific and selective field in the targeted tissue having an amplitude of between 1 mV/cm and 80 mV/cm that substantially down-regulates the gene expression of MMP protein in said targeted tissue as measured by mRNA production, said signal source controlling and duration of time of application of said at least one specific and selective signal for a predetermined duration of time and controlling and varying the duty cycle of said at least one specific and selective signal from approximately 5% to 100% so as to selectively down-regulate gene expression of MMP in the targeted tissue as measured by mRNA as result of application of the specific and selective field. 
     
     
         15 . The device of  claim 14  wherein the signal source is programmable such that fields generated during various modes can be sequentially applied to the targeted tissue for various periods of time and in various orders. 
     
     
         16 . The device of  claim 14  further comprising means for attaching the electrodes, coils, or other field generating devices to the body of a patient in the vicinity of bone tissue. 
     
     
         17 . The device of  claim 14  further comprising means for attaching the signal source to the body of a patient. 
     
     
         18 . The device of  claim 14  wherein the electric field generated by application of said at least one specific and selective electric signal to the electrodes, coils, or other filed generating devices is applied to said targeted tissue via capacitive coupling or inductive coupling. 
     
     
         19 . The device of  claim 14  wherein the specific and selective electric signal has a sine wave configuration. 
     
     
         20 . A method of treating tumors or cancerous tissue, comprising the steps of exposing targeted tissue to the specific and selective field generated by the device of  claim 14  so as to down-regulate gene expression of MMP protein in the targeted tissue as measured by mRNA production in the targeted tissue.