WO1998016215A1

WO1998016215A1 - Use of essential fatty acids for the treatment and prevention of radiation damage to erythrocytes

Info

Publication number: WO1998016215A1
Application number: PCT/GB1997/002441
Authority: WO
Inventors: David Frederick Horrobin; Catherine Ann Scott
Original assignee: Scotia Holdings PLC
Current assignee: Scotia Holdings PLC
Priority date: 1996-10-14
Filing date: 1997-09-11
Publication date: 1998-04-23
Anticipated expiration: 1999-04-14
Also published as: ZA978226B; AU4130597A; GB9621373D0

Abstract

Use of at least one n-6 essential fatty acid and/or at least one n-3 essential fatty acid and/or at least one n-3 essential fatty acid in the preparation of a medicament for countering red cell damage and/or tissue hypoxia during radiotherapy, and/or consequent fatigue and the method of countering such by its administration.

Description

USE OF ESSENTIAL FATTY ACIDS FOR THE TREATMENT AND PREVENΗON OF RADIAΗON DAMAGE TO ERYTHROCYTES

Field of Invention

The invention relates to fatty acid treatment

Background

Much attention has been paid in previous patent applications of the applicants and in general literature to fatty acids

The essential fatty acids of the n-6 and n-3 series are of particular importance These acids, and their conversion pathways in the body are shown in Table 1

TABLE 1

n-6 EFAs n-3 EFAs

18 2n-6 18 3n-3 Linoleic acid (LA) α-hnolenic acid (ALA)

Φ δ-6-desaturase Φ

18 3n-6 18 4n-3 γ-Linolenic acid (GLA) Stearidonic acid, (SA)

Φ elongation Φ

20 3n-6 20 4n-3

Dihomo-γ-linolemc acid Eicosatetraenoic acid

(DGLA)

Φ δ-5-desaturase Φ

20 4n-6 20 5n-3 Arachidonic acid (AA) Eicosapentaenoic acid (EPA)

Φ elongation Φ

22 4n-6 22 5n-3 Adrenic acid (AdrA)

Φ δ-4-desaturase Φ

22 5n-6 22-6n-3 Docosahexaenoic acid (DHA) The acids, which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. LA z,z-octadeca - 9,12 - dienoic acid or DHA z,z,z,z,z,z - docosa- 4,7,10,13,16,19 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient. Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances.

Much attention further has been given to radiotherapy as one of the commonest methods of treating cancer. It is effective in many patients. The main problem is the damage that the radiation does to normal tissues. This causes adverse effects in itself and also limits the dose of radiation which can be administered, often leading, as regards the effect on the cancer, to a sub-therapeutic treatment.

Present Work

Improved targeting and treatment schedules have led to reduced exposure of many normal tissues to radiation. However, one normal tissue simply cannot be protected and that is the blood which circulates through the tumour and immediately adjacent areas. Little attention has been paid to this because most of the cells in blood are red cells which are non-nucleated. It is usually thought that nucleic acids are the main target for radiation damage and therefore that red cells will be little affected.

Thus in previous investigations by ourselves and by many others, including those leading to our patent applications EP-A-0416855 and EP-A-0609064 the possibility of damage to red cell membranes was not considered as important. However, we have now thought to look for effects and have found to our surprise that human red cells are severely damaged by loss of fatty acids during radiotherapy. We have further found that the damage can be countered by administration of fatty acids, particularly the unsaturated fatty acids naturally present in red cell membranes. Since these unsaturated fatty acids are absolutely required for the maintenance of normal membrane fluidity and flexibility, the functional consequences are important. Red cells have a diameter greater than the diameter of most of the capillaries in the body. In order to pass through the capillaries quickly to deliver oxygen to the tissues, the red cells must be fluid and flexible so that they can squeeze through. If the red cells become stiffer because of loss of unsaturated fatty acids, they will pass through the capillaries more slowly or not at all, thus reducing the rate of delivery of oxygen to the tissues. This is undesirable in principle but in the context of radiotherapy may have particular adverse consequences.

First, the efficiency of cancer cell killing by radiotherapy depends on a good oxygen supply to the tissues. The more oxygen there is, the more effectively will the cancer cells be destroyed, but damaged red cells will not deliver it effectively. Further, cancers often have precarious blood supply leading to resistance to radiation. Stiff red cells will exaggerate the problem by reducing further the supply of oxygen.

A second problem relates to the fatigue which is characteristic of patients undergoing radiotherapy and which has never been fully explained. Stiff red cells and a reduction in the oxygen supply to the tissues are important contributors to this fatigue.

Statement of Invention

Thus, in one aspect the invention provides a method of countering red cell damage due to radiotherapy by the administration of essential fatty acids and, correspondingly, the use of essential fatty acids for the preparation of medicaments for the prevention and treatment of red cell damage due to radiotherapy.

In a second aspect, the invention provides a method of countering post- radiotherapy fatigue by the administration of such acids. This aspect likewise, embraces the use of the essential fatty acids for the preparation of a medicament for the prevention of treatment of post-radiotherapy fatigue.

In a third aspect, the invention provides a method of countering hypoxia in radiotherapy by the administration of the acids. This aspect, again, embraces the use of the acids for the preparation of a medicament for the prevention or treatment of tissue hypoxia in radiotherapy.

The most important EFAs in the cell membranes are those beyond the first delta-6-desaturase rate-limiting step in both series, that is gamma-linolenic acid and its metabolites in the n-6 series and stearidonic acid and its metabolites in the n-3 series. Further, while n-6 or n-3 fatty acids alone may confer some benefit, optimum results are achieved with n-6 and n-3 EFAs together because both are required for normal membrane structure. Particularly appropriate n-6 EFAS are GLA, DGLA and AA, while particularly effective n-3 EFAs are SA, EPA, DPA and DHA. The parent EFAs, linoleic and alpha-linolenic acid may be used optionally if desired.

The fatty acids may be administered in any form which allows their incorporation into the blood after administration by oral, enteral, parenteral, topical or any other appropriate route. Although the list is not exhaustive, useful forms include the free fatty acids, salts including lithium salts, glycerides including mono di and triglycerides, amides, adducts with amines including meglumine, ascorbic acid and niacin derivatives, mono and diesters of the diols of our previous patent applications WO 96/34836 (PCT GB 96/01053) and WO 96/34855 (PCT GB 96/01052), cholesterol esters and phospholipids. The doses of the acid(s) may range from 1 mg to 100 g per day, preferably 1 mg to 20 g and very preferably 50 mg to 5g, suitably delivered in dosage unit forms or as preparations containing 0.1 to 10% by weight of the fatty acids.

Formulation Examples

The following are examples of suitable presentations for use as described against radiation damage to the red cells of the blood :-

1. A soft or hard gelatin capsule containing 50-500 mg of GLA in any appropriate form with the recommended dose being 2 to 10 capsules/day.

2. A tablet of pastille containing 100-200 mg of GLA in any appropriate form with the recommended daily dose being 4 to 8 per day.

3. A cream, ointment, whip, foam, pessary, suppository, or emulsion or any other appropriate formulation for topical adminsitration containing 0.1 to 10% by weight of GLA, used to deliver a daily dose as above.

4. An emulsion or solution for parenteral or enteral administration containing 1% to 30% of GLA by weight, used as last.

5. A foodstuff such as a granule, cream, gel, pastille, flake, powder or other form known to those skilled in the art containing 0.1 to 10% of GLA by weight used as last.

6-10 As 1-5 but with the active ingredient DGLA or AA, alone or in association with GLA.

11-15. As 1-5 but with the active ingredient SA, EPA, DPA or DHA rather than GLA. 16-25 As 1 - 10 but in addition containing EPA or DHA in an amount of 10-300 mg per unit dose, or 0.1% by 10% by weight in formulations for topical, enteral, parenteral or food use.

26-50. As 1-25 but in addition containing 1- 500 mg of LA and/or ALA per unit dose, or 0.1 to 10%) by weight in formulations for topical, enteral, parenteral or food use.

Clinical Study

The use of the invention is illustrated further in the following clinical study.

A group of 404 women undergoing radiotherapy after surgery for breast cancer was entered into a study in which members of the group were randomised to receive a sunflower oil placebo, containing the parent n-6 unsaturated fatty acid, linoleic acid, or active treatment with the highly unsaturated fatty acids of cell membranes or their immediate precusors. These fatty acids are dihomogammalinolenic acid (DGLA, 20:3 n-4) and arachidonic acid (AA, 20:4 n-6) of the n-6 series and eicosapentaenoic acid (EPA, 20:5 n-3), docosapentaenoic acid (DPA, 22:6 n-3) and docosahexaenoic acid (DHA, 22-6 n-3) of the n-3 series. AA and DGLA for example can be formed from linoleic acid but the first step in this pathway, the conversion of linoleic acid to gamma-linolenic acid (GLA, 18:3 n-6) is very slow. Thus for example the administration of linoleic acid therefore has little impact on DGLA and AA, whereas GLA can raise their levels substantially.

The placebo provided 3000 mg of linoleic acid per day whereas active treatment provided GLA (480 mg per day), EPA (96 mg/day) and DHA (64 mg/day). Patients were subjected to conventional radiotherapy regimes, usually lasting 6-8 weeks and blood samples were taken at baseline and at 12 weeks when all radiotherapy was completed. Red cell fatty acid composition was measured in both samples. The results were striking. In the placebo as shown in table 2, the five key fatty acids fell by 20-30% during radiotherapy, leading to a substantial increase in red cell stiffness. In contrast, the reductions for all five were much less in the active treated group, Thus the co-administration of GLA, EPA and DHA substantially reduce the red cell damage. This is likely to lead to improvement in tissue blood flow, an improvement in the efficacy of radiotherapy and a reduction in fatigue. Similar effects are to be expected with a combination of a single n-6 acid and a single 1-3 acid, and worthwhile effects with an n-6 or an n-3 acid alone.

Table 2:- Percentage changes from baseline for the key highly unsaturated fatty acids of red cell membranes, p values are for differences between the change in the active group and the change in the placebo group (Student's test).

Fatty Acid Change on Placebo Change on Active p

0-12 weeks 0-12 weeks

20:3 n-6 (DGLA) ■14.8% -1.3% 0.004

20:4 n-6 (AA) -21.5% -14.0% 0.002

20:5 n-3 (EPA) -31.8% -15.8% 0.001

22:5 n-3 (DPA) -31.8% -12.6% 0.001

22.6 n-3 (DHA) -21.5% -5.0% 0.02

Claims

1. Use of one or more n-6 essential fatty acids and/or one or more n-3 essential fatty acid in the preparation of a medicament for countering red cell damage and/or tissue hypoxia and/or post-treatment fatigue, arising from radiotherapy, and therapy for such purposes by its administration in effective amounts.

2. Use or therapy according to claim 1 wherein the fatty acids are selected from acids beyond the first rate-limiting step in the bodily conversion of essential fatty acids (the δ-6 desaturation step).

3. Use or therapy according to claim 2 wherein n-6 fatty acids are selected from GLA, DGLA and AA.

4. Use or therapy according to claim 2 or 3 wherein n-3 fatty acids are selected from SA, EPA, DPA and DHA.

5. Use or therapy according to claim 2, 3 or 4 wherein the medicament further comprises LA and/or ALA.