1. Field of Invention
This invention relates generally to the electrochemical treatment of tissues by applying a voltage across electrodes to cause a current to flow through the tissue. In one embodiment of the invention, the current flow produces an electrochemical reaction yielding multiple reaction products some of which act as cytotoxic agents to destroy cancer cells, the voltage being regulated to optimize the yield of those cytotoxic agents having the greatest efficacy. In another embodiment, fed into the tumor is one or more reagents which when current flows through the tumor react with the material of an electrode to yield a cytotoxic agent. Alternatively, the surface of the electrode can serve as a catalyst for the formation of the cytotoxic agents.
2. Status of Prior Art
Oncology is the branch of medical science dealing with tumors. The prime concern of the present invention is with treatment of tumors and other forms of neoplasm. The distinction between a benign and a malignant tumor is that the latter will invade surrounding tissues and spread or metastasize to other sites, whereas a benign tumor will not spread.
The common practice in the field of oncology to cure or ameliorate a cancerous condition is by appropriate surgery, radiotherapy or chemotherapy, sometimes used singly, but more often in combination.
Radiotherapy which produces its biologic effect on cancerous tissue by ionization is carried out by megavolt energy radiation in the form of X-rays from a linear accelerator or gamma rays from a cobalt 60 source. Radiation is highly penetrating, but in order to reach the region of the tumor being treated, the radiation beam must pass through regions containing healthy tissue and may therefore destroy these as well as the malignant tumor.
Chemotherapy dictates the utmost care in monitoring and controlling the administration of cytotoxic drugs, for the biochemistries of malignant and non-malignant cells are so similar that it is difficult to destroy cancerous cells without concurrently destroying healthy cells. The adverse effects of chemotherapy are notorious.
One of the most potent an widely used substances in the chemotherapy today is cisplatin (Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug, Bernhard Lippert, Ed, Wiley, VCH, Weinheim, 1999). It is a platinum compound, first observed to form by electrochemical reaction in a cell culture by Barnett Rosenberg et al (Inhibition of Cell Division in Escherichia coli by Electrolysis Products from Platinum Electrode, Nature, Vol. 205, pp. 698-9, 1965). This work resulted in discovery of cisplatin as cytotoxic agent, highly effective in cancer treatment. Follow-up work by Rosenberg and co-workers showed that several platinum compounds have antitumor properties (Platinum Compounds: a New Class of Potent Antitumor Agents, Nature, vol. 222, pp. 385-6, 1969). Some other platinum group compounds have also been shown to destroy cancer tissue.
Both cisplatin and other platinum compounds are manufactured synthetically and administered, in most cases, intravenously. The major problem with chemotherapy drugs is a lack of selectivity (both cancerous and normal tissues are affected) and high toxicity for healthy tissue. In the case of cisplatin, there are severe side effects in form of kidney toxicity and nausea and vomiting. The kidney toxicity is currently controlled by hydration and the nausea and vomiting by drugs. Thus the intravenously administered doses currently used are limited by patient""s tolerance to the drug rather than being optimized for dose effectiveness in cancer treatment.
In the case of solid tumors, experimental efforts are being made to minimize the side effects through a local delivery either through an injection of the anticancer agent directly to the tumor or through release of various anticancer agents encapsulated in e.g., hydrogels.
It is also known to destroy malignant tumors by elevating the temperature of the tumor to a level at which cancerous cells are destroyed. One method used for this purpose is to focus a beam of microwave energy of the type generated in a microwave oven onto the tumor. But the drawback of this technique is that healthy tissues through which the beam must pass to reach the tumor have a higher moisture content than the interior of the tumor and are therefore more reactive to microwave energy.
The problem with surgery to excise a malignant tumor is that the location of the tumor, as in the case of a tumor in the brain, may be such as to render the tumor inoperable. But even where the tumor is accessible to the surgeon""s scalpel, then in order to reach this tumor, one must cut through and damage healthy tissue. Moreover with surgery, one cannot be sure that all malignant cells have been removed, and the residual cells may metastasize.
The primary concern of the present invention is with in situ electrochemical treatment of a malignant tumor, the treatment acting to destroy the tumor with minimal damage to regions surrounding the tumor.
In an existing electrochemical treatment (ECT), electrodes are implanted at spaced positions in or around the malignant tumor to be treated. Applied across these electrodes is a low dc voltage usually having a magnitude of less than 10 volts, causing a current to flow between the electrodes through the tumor. Due to an electrochemical reaction, reaction products are yielded which include cytotoxic agents that act to destroy the tumor.
In the ECT technique disclosed by Li et al., in Bioelectromagnetics 18:2-7 (1997), in an article xe2x80x9cEffects of Direct Current on Dog Liver: Possible Mechanisms For Tumor Electrochemical Treatmentxe2x80x9d two platinum anode and cathode electrodes were inserted in a dog""s liver with a 3 cm separation therebetween. Applied across these electrodes was a dc voltage of 8.5 volts, giving rise to an average current through the liver of 30 mA. This was continued for 69 minutes, with a total charge of 124 coulombs. The concentration of selected ions near the anode and cathode were measured. The concentration of Na+ and K+ ions were found to be higher around the cathode, whereas the concentration of C1xe2x88x92 ions was higher around the anode. Water content and pH were determined near the anode and cathode, the pH values being 2.1 near the anode and 12.9 near the cathode. The released gases were identified as chlorine at the anode and hydrogen at the cathode. The series of electrochemical reactions which took place during ECT resulted in the rapid and complete destruction of both normal and tumor cells in the liver.
Another example of ECT appears in the article xe2x80x9cElectrochemical Treatment of Lung Cancerxe2x80x9d by Xin et al. in Bioelectromagnetics 18:8-13 (1997). In this ECT procedure platinum electrodes were inserted transcutaneously into the tumor, the voltage applied thereto being in the 6-8 volt range, the current being in the 40 to 100 mA range, and the electric charge, 100 coulombs per cm of tumor diameter.
According to this article, the clinical results indicate that ECT provides a simple, safe and effective way of treating lung cancers that are surgically inoperable and are not responsive to chemotherapy or radiotherapy.
Also disclosing an ECT technique is the patent to Anderson U.S. Pat. No. 5,360,440 In Situ Apparatus For Generating An Electrical Current in a Biological Environment.xe2x80x9d
Electrochemical reactions as a function of pH and electrode potential can be predicted by means of a Pourbaix diagram, as disclosed in the Atlas of Electrochemical Equilibria in Aqueous Solutionsxe2x80x94Pergamon Press, 1966xe2x80x94by Pourbaix. Reaction products of electrolysis of water include hydrogen, oxygen, and hydrogen peroxide (H2O2).
In the text Methods in Cell Biology, Vol. 46xe2x80x94Cell Deathxe2x80x94published by Academic Press, 1995, it is noted (page 163), that hydrogen peroxide has been reported to be an inducer of cell death in various cell systems. This type of cell death is attributed to the direct cytotoxicity of H2O2 and other oxidant species generated from H2O2.
The present invention also involves an electrochemical technique for cancer treatment in which cisplatin, a highly-effective cytotoxic agent, or other cytotoxic agents are produced in situ. Of background interest therefore is the article in the Jul. 5, 1999 issue of The Scientist xe2x80x9cFrom Basic Research to Cancer Drug, The Story of Cisplatin.xe2x80x9d
In view of the foregoing, the main object of this invention is to provide an electrochemical technique and apparatus for carrying out this technique adapted to treat, in situ, a tissue to destroy all or a selected portion thereof for the benefit of the patient, and most especially for treating a malignant tumor or other form of neoplasm in order to destroy cancerous tissues with minimal damage to healthy tissues.
A significant feature of one embodiment of this invention in which a voltage is applied across working and counter electrodes implanted in or otherwise applied to the tissue being treated, is that the voltage is controlled during electrochemical reactions produced in the tissue to optimize the yield of those reaction products which act as cytotoxic agents destructive of cells of that tissue type.
Also an object of this invention is to provide method and apparatus for carrying out an ECT procedure concurrently with chemotherapy treatment to subject the tissue being treated to one or more cytotoxic chemicals from a chemotherapy source as well as from reaction products yielded by an electrochemical reaction.
Yet another object of this invention is to provide a method and apparatus for carrying out an ECT procedure in conjunction with photochemically-activated drugs delivered to the tissue, especially a malignant tumor, whereby as current passes through the tumor to produce an electrochemical reaction, the tumor is at the same time exposed to light to activate the drugs.
Briefly stated, these objects are attained by a technique and apparatus therefor adapted to treat in situ a specific tissue, especially a malignant tumor, use being made of strategically placed electrodes. In one embodiment of the invention, there is applied across the electrodes a voltage causing a current to flow through the tissue producing an electrochemical reaction yielding multiple reaction products, at least one of which is a cytotoxic agents destructive of the particular tissue cells desired to be eliminated. Coupled to the electrodes is a control unit which acts to regulate the voltage applied thereto so as to optimize the yield of those cytotoxic agents having the greatest efficacy. Strategic placement of the electrodes means that they are placed in situ effective to cause current flow through the tissue, and preferably to minimize current flow through other tissues not desired to be treated.
In another embodiment, one or more reagents are delivered to the tissue treated when current flows therethrough and react with the material of an electrode to yield a cytotoxic agent in situ, or an inactive isomer of a cytotoxic agent, which when exposed to light becomes activated.
In yet another embodiment one or more reagents are delivered to the tissue and the surface of the electrode serves as a catalyst for the formation of the cytotoxic agents in situ.
In still another embodiment, the electrode composition itself (such as the anode whose composition goes into solution during the electrochemical treatment) is a cytotoxic agent, or reacts with a second composition delivered locally to form a cytotoxic composition in situ.