AU595514B2 - Use of an aqueous chlorite matrix solution for the treatment of tumors - Google Patents

Abstract

The solution of a chemically stabilized chlorite matrix is administered intravenously and/or locally for treating tumours.

Description

AUSTRALIA

Patents A ct ,59551 4 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: SC L a Lodged: Complete Specification Lodged: Accepted: Published: LODGED A; SUB.- Fp 10 **Se Priority .Related Art: sad is 1 hr *5 S S 5* S S

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APPLICANT'S REF.: 4471 B2 Name(s) of Applicant(s): OXO Chemie GmbH Address(es) of Applicant(s): Acua...ntr~) Adrs fo0evc s MaaBstrasse 24, 6900 Heidelberg, Federal Republic of Germany Dr. Friedrich W. Kiihne Prof. Dr. Dr. Kurt-Wilhelm Stahl PHILLIPS, ORMONDE AND FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne, Australia, 3000 Complete Specification for the invention entitled: USE OF AN AQUEOUS CHLORITE MATRIX SOLUTION FOR THE TREATMENT OF TUMORS The following statement is a full description of this invention, including the best method of performing it knowvn to applicant(s): P19/3184 The invention relates to the use of a chlorite matrix solution for the treatment of tumors.

In the conventional chemotherapeutic treatment of tumors it has to be accepted that there is a considerable 5 risk of side effects, which impair the quality of life, in order to obtain an objectively measurable tumor re- Sgression.

*The object of the invention is to diminish this risk of side effects of chemotherapeutic and radio- 10 therapeutic treatments of tumors using a composition with, at the same t.ime, an improvement or at Least a maintenance of the therapeutic efficacy of the treatments.

This object is achieved by the use of a composition consisting of an aqueous solution of a chemically stabilized chlorite matrix for intravenous and topical administration in tumor treatments.

The use of the composition- can be- obie ith radiotherapy, with chemotherapy, with radio- and che therapy, and with chemotherapy and hyperthermia.

20 A chlorite matrix with activated oxy n is disclosed in German Offenlegungsschrift 3,2 ,389 and has already been used successfully as a und-treatment agent.

It has now been found, surprisin y, that a chemically stabilized chlorite matrix c be used with good results for tumor treatments, i eing possible for the matrix to be stabilized by xygen or another element of groups VI a b of the eriodic table or in another manner. It is known th the oxygen supply to malignant tumors may very gr tly influence the efficacy of various therapeutic mea res, such as ionizing radiation or particular chemo- -1At Ib It is an object of the present invention to provide a stabilized aqueous tumor therapeutic solution of a chlorite matrix with a chlorite concentration of 12 to 72 pmol 2 /ml prepared by reaction of the following components: sodium chlorite solution sodium hypochlorite solution chloryl sulphuric acid sodium perborate or percarbonate and sodium peroxide.

The method can preferably be combined with radiotherapy, with chemotherapy, with radio- and chemotherapy, and with chemotherapy and hyperthermia.

A chlorite matrix solution with activated oxygen is disclosed in German OffenLegungsschrift 3,213,389 for which the corresponding US Patent is No. 4,507,285 and has already been used successfully as a wound-treatment agent. The term "chlorite matrix solution" as used herein the description and claims is a tetrachlorodecaoxygen (TCDO) in an isotonic water solution. The TCDO anion complex constitutes a negatively charged matrix of chlorine with stabilized oxygen entrapped therein (C1 4 0 10 )n 1,ul of WF10 (an isotonic TCDO solution in H 2 0) diluted 50-fold in the presence of -5 M hemoglobin in PBS liberates 11.5n moles of 02 and S-5 2 in the presence of 10 M hemine, fractionates 2.8 x 102p moles ethene from 1-aminocyclopropane carboxylic acid.

It has now been found, surprisingly, that a chemically stabilized chlorite matrix can be used with good results for tumor treatments, it being possible for the matrix to be stabilized by oxygen or another element of groups VI a b of the periodic table or in another manner. It is known that the oxygen supply to malignant tumors may very greatly influence the efficacy of various therapeutic measures, such as ionizing radiation or particular chemotherapeutics.

Experiments have shown that it is possible 1 2 to obtain a Pasteur effect on intravenous administration of an isotonic solution of the chLorite matrix, the action of the chlorite matrix being direct and/or indirect.

There is a direct and indirect action when the stabilizer of the chlorite matrix is oxygen. The action is indirect when stabilization is effected by another element of group VI a b of the periodic table or in another manner, for example a high pH.

It has been found that the chlorite matrix acts in practice as a biochemical even in the micromolar range and below, and thus need not be supplied in excessive concentrations in order to display its action. In this 'context, it is assumed that an activated, non-toxic oxygen species is formed, by which an increase in the blood S 15 flow in peripheral hypoxic areas owing to vasodilatation, and an oxygen-saving measure in the mitochondria is obtained. This action probably contributes to an increase in the oxygen levels in the tissue and in the body fluids S, 2 after administration of the chlorite matrix.

20 If chemotherapy and radiotherapy are combined with chlorite matrix treatment, it is possible considerably to reduce the doses of chemotherapeutic agents and of the irradiations and thus the risk of side effects to achieve the same results.

ExfpK-r im-e al -pe-ru- t-5 o nn th e-antitu-mo eff icacy ofstabilized chlorite matrix.

Use was made of an isotonic solution of xygenstabilized chlorite matrix which contains .8 x 102 oxidation units measured by gas chromato aphic determination of the ethylene liberated from uitab e indicator molecule. Experiments on sever transplantation tumor models in mice and rats have -town that the chlorite matrix solution slows down tumor growth as a function of the dosage (dos s: 0.17, 0.34 and 0.68 ml of chlorite matrix so ion per kg of body weight, administered 1 x a d parenterally). The inhibitory action of metastai~ I _II_ 2a Accordingly, in a further preferred aspect of the present invention, there is provided a method for the treatment of tumors which utilises a chemically stabilized chlorite matrix in combination with radiation therapy. This combined use results in a decrease in the number of therapy failures and a significant remission of infiltration.

Example 1 Experimental results on the antitumor efficacy of stabilized chlorite matrix.

Use was made of an isotonic solution of oxygen-stabilized chlorite matrix which contains 2.8 x 10 2 oxidation units measured by gas chromatographic determination of the ethylene liberated from a suitable indicator molecule. Experiments on several transplantation tumor models in mice and rats have shown that the chlorite matrix solution slows down the tumor growth as a function of the dosage (dosages: 0.17, 0.34 and 0.68 ml of chlorite matrix solution per kg of body weight, administered 1 x a day, parenterally). The inhibitory action of metastasizing solid tumors relates not only to the primary tumor a a but aLso to the secondaries (metastases).

The testing for antitumor efficacy produced positive results with the following transplantation tumors: Lewis Lung, adenocarcinoma of the C 57 81/6 mouse, Harding- Passey sarcoma of the C 57 81/6 mouse, Friend virus Leukemia of the NMRI mouse and L 5222 leukemia of the BD IX rat. It was noticed with all the tumors mentioned here that although the weight reduction during treatment with the stabilized chlorite matrix was less dramatic than for the positive controls treated with cycLophosphamide, the animals treated with chlorite matrix solution showed a markedly better and more active general condition than the animals treated with the cytotoxic chemotherapeutic.

Stabilized chlorite matrices are activated by 15 complexation with macrocyclic tetrapyrroLe-containing biomoLecuLes to give compounds with eLectron affinity.

It is known of compounds with electron affinity that they act as radiation-sensitizers in the radiothere'eutic treatment of maLignant tumors (reference: W. i:orschen, 20 K. Gewehr, L.E. Feinendegen, Med. Physik, voLume 2, pages 467-479/1976). This pharmacoLogicaL property has been confirmed by initial positive findings in radiotherapy under previous parenteraL treatment with the chlorite matrix solution of patients with tumors which responded poorly to radiotherapy.

The therapeutic tests on transplantation tumors in animal experiments have shown that the antitumor efficacy of stabilized chlorite matrices is not a cytotoxic or cytostatic effect. On the contrary, the stabilized chlorite matrices influence, on the one hand, the body's own defensive sy ;tem and, on the other hand, the experiments carried out with L 5222 and Friend virus leukemia show that the chlorite matrices have a reverting actior.

on the malignant ceLL phenotype of the tumors. These points of attac', which are of an entireLy different nature to those of the conventional chemotherapeutics, lead to the conclusion that additional treatment with stabilized chlorite matrices can potentiate the antitumor effect of classical chemotherapeutics.

4 Example 2 Prior i.v. administration of TCDO solution before radio therapy A method is described in which an intravenous application of a substance with the test name of WF10 known to be immuno-modulatory was carried out in humans in addition to the usual radio-therapy of collum carcinoma in stage IIIb according to the Figo method. The remission of the tumor mass was significantly better with the combined therapy, and the rate of treatment failure after the series of treatment was completed was significantly lower. The results of long term examinatic of these patients will 0*0@ ultimately inform us as to whether the survival of the patients which have been treated with the combined therapy can be considerably improved.

S A clinical randomized study of the radiosensitization affect of a chlorite matrix substance, WF10 (TCDO) was carried out. This was a combined therapy for collum carcinoma consisting of radio-therapy and intravenous administration of TCDO. WF10 (an isotonic TCDO solution in water) was administered intravenously two hours prior to radiation. 1 pl of WF10 diluted 50 fold in the presence of -5 10 M hemoglobin in PBS liberates 11.5 n moles 02 and -5 in the presence of 10 M hemine, fractionates 2.8 S X 10 p moles for ethane from 1-aminocylcopropane carboxylic acid (ACC). A test group of animals received S500ml of 5% glucose plus 0.2 ml of WF10 per kg of body weight, while the control group received 500 ml of glucose after half an hour of stabilization at 5% glucose only.

For radiation treatment, a combined Tele-brachy radiotherapy was used. For Tele-therapy, 23 individual positions in a set area were tested over a total treatment period of 31 days. A computer planned maximum radiation dose of 46 Gy was used for each of the parameters for precise distribution of the dose.

Brachytherapy was carried out with a high dose intracavitary on the vagina and uterus with topical applications. The reference points were situated 1 cm away 1 5 from the applicator surface. This treatment was carried out on the vagina every fourth day and similarly on the uterus with an interval of 3 days. When bracy-therapy was carried out, teletherapy was not.

This test was performed to observe the following: 1. Tolerance of the WF10 substance over a longer period of treatment; 2. Behaviour of a radiated tumor under a combined radiation WF10 therapy; 3. Effect of combined treatment on the blood cells; 4. Influence of the substance WF10 on the pO2; and Behaviour of the t-lymphocyte sub populations T4 and T8.

For radiotherapy, brachytherapy high dose rate was 6 x 8 Gy intracavitary (vagina) and 2 x 10 Gy intracavitary (uterus) while beam therapy was carried out with a linear accellerator with two opposite fields.

S. Observations made on remission rates every 5th day show that there were clear and significant differences in the local remission rate of the tumor infections, reduction of which was exclusively determined by palpation.

se* Remission of the tumor infiltration in the collum of the uterus and the vagina occurred some-what similarly in both observed and controlled groups.

e.During radiation treatment, there was a slight drop in the average erythrocyte values in both groups when exposed to increasing levels of radiation. Coincident with the drop S in erythrocyte values was a decrease in leucocytes in both groups following the same treatment. This was reflected in a similar drop from 40 to 45% of the number of lymphocytes when radiation was increased from 0 to 40 Gy. Of the Slymphocyte sub-population, an increase in the number of T4 helper cells and thereby normalization of the T4/T8 index was significantly greater and faster in the WF10 (TCDO) group than the control group. In the WF10 group the increase amounted to 19% while the control group remained at 6.7%.

Hence by virtue of the significant results that were SUS? obtained statistically, there was a significantly greater I I~ 6 increase in the capillary pO 2 in the group being treated with WF10 than in the control group. These parameters support the suggestion that the collum carcinoma is sensitized to radiation.

Tolerance to the substance WF10 when it was administered over a period of 30 days was significant, there were no changes in the blood cells compared to the control group.

The clinical results show with great clarity that it is possible to significantly reduce the number of therapy failures when a combined WF10 radiation therapy is used.

Furthermore, the varying remission tendency of the infiltration in the various regions which points to an additional mode of action of a WF10 substance. There is the o* o. possibility of a radio sensitizing factor and also of an o immunological factor. The stimulation of macrophages alone can cause the radiation necroses caused by radiation in the tumor tissue area to be sloffed off faster. Also a change in the number of T4 helper cells versus the control group points to an immunological effect, which can be interpreted as being due to the macrophages.

Stenosis of the urinary tracts of the large blood vessel, tending towards thrombosis and the accompanying subjective complaints such as pain could be more effectively treated with the combined form of therapy than with radiation therapy alone. The results of patient examinations on a long term basis will prove whether a permanent influence can be made on the survival rate of the patients.

Claims (3)

1- I

7- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. A chemically stabilized aqueous tumor therapeutic solution of a chlorite matrix with a chlorite concentration of 12 to 72 pmol C10 2 /ml prepared by reaction of the following components: sodium chlorite solution sodium hypochlorite solution chloryl sulphuric acid sodium perborate or percarbonate and sodium peroxide. 2. A solution as claimed in claim 1 in a pharmaceutically acceptable carrier. *eos "as 3. A solution as claimed in claim 1 substantially as hereinbefore described with reference to any one of the S* n examples. 4. A method of treating tumors in patients which comprises administering intravenously or applying topically an effective amount of a solution as claimed in claims 1 to 3. A method of treating tumors in patients as claimed in claim 4 which further comprises radiotherapy treatment. oo* 6. A method of treating tumors in patients as claimed in claim 4 or 5 which further comprises chemotherapy treatment. 7. A method of treating tumors in patients as claimed in cases: any one of claims 4 to 6 which further comprises hyperthermia.

8. A method as claimed in claim 4 substantially as hereinbefore described with reference to any one of the examples. C a DATED: 19 January, 1990 PHILLIPS ORMONDE FITZPATRICK Attorneys for: OXO CHEMIE GmbH 0347v