IE45653B1 - Anthraquinones for cancer therapy - Google Patents

Description

This invention relates to a substance, and to a composition containing it, for use in a method of treatment of the human body by therapy, for the alleviation, palliation or cure of cancer.

The substances for anti-cancer use according to this invention, and which may be in the pharmaceutical compositions, are the anthraquinones having the general formula: NH-R-NH-ROH NH-R-NH-ROH when R is an alkylene group having 1 to 4 carbon atoms. The preferred compound of this invention is that wherein each R is an ethylene group.

The anthraquinone of formula 1 wherein each R is an ethylene group is itself a compound known as a dyestuff, from United States Patent No. 2051004. We have found, however, that it shows presumptive activity against leukaemia in mice, used as standard test mammals» Each of the compounds of formula 1, and their pharmaceutically acceptable salts, oan be expected to show activity against a broad range of cancer diseases, - 3 and especially blood cancer disease such as leukaemia, in humans at doses below toxic levels.

The anthraquinone compounds of formula 1 may be prepared as described in Example 59 of United States Patent No. 2051004, or by reacting 2 moles of an N-aminomethyl-alkanolamine with 1 mole of leuco quinizarine and oxidising the resulting product with, e.g. air.

The N-aminoalkylalkanolamines useful in preparing the anthraquinones of formula 1 are: N-aminomethylmethanolamine (H2NCH2NHCH2OH), N-aminoethylethanolamine (H2NCH2CH2NHCH2CH2OH), N-aminopropylpropanolamine (h2nch2ch2ch2nhgh2ch2ch2oh) and N-aminobutylbutanolamine (H2NCH2CH2CH2CH2NHCH2CH2CH2CH2OH).

While the reaction mechanism requires 2 moles of N-aminoalkylalkanolamine per mole of leuco quinizarine, it is generally preferred to employ an excess, e.g. 2.5 to 3 moles of the N-aminoalkylalkanolamine to ensure formation of the desired product.

Conveniently, these anthraquinones can be prepared by dissolving the leuco quinizarine in a solvent, such as ethyl alcohol, charging the N-aminoalkylalkanolamine with agitation and heating to about 75-8O°C for a time sufficient to allow the reaction to occur. Thereafter, oxygen is bubbled through the solution until the leuco product is oxidised. The solution is cooled to about 1O°C, filtered, washed with alcohol and dried.

The pharmaceutical use of the anthraquinone of formula 1 consists in administering them to a patient suffering from cancer. The anthraquinones are suitably - 4 administered - as such or in the form of a salt - as one ingredient of a composition containing also a pharmaceut ically acceptable carrier.

The pharmaceutically acceptable salts include the acid salts, for example, those of hydrochloric, citric, succinic, maleic, tartaric, acetic, and like acids.

Of the acid salts, the acetate and hydrochloride are preferred. Such salts are pharmaceutically acceptable in the sense of having no substantially different ' activity or toxicity compared to the base.

The modes contemplated for carrying out the invention include pharmaceutical compositions and process of administration thereof.

Solutions of the principal active ingredient as a free base or salt can be prepared in water or in water suitably mixed with, for example, surfactants. The preferred compound, where R is ethyl in the above formula, is slightly soluble in water. It can, for example, be converted to a partial acetate having a pH in agueous solution of about 7.4 which, on analysis, shows about 1¾ acetic acid residues/anthraquinone nucleus. A diacetate may also be produced having a pH in aqueous solution of about 6.2. The diacetate is soluble in water to the extent of about 400 mg/millilitri of water. . The base or various salts may be made more soluble by the addition of surfactants such as hydroxypropylcellulose to the composition. Dispersions can also be prepared ih glycerol, liquid polyethylene glycoli and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. 43653 - 5 The pharmaceutical compositions can be in forms suitable for injectable use, which forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of micro10 organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polythene glycol, and the like), suitable mixtures thereof, and vegetable oils.

The proper fluidity can be maintained, for example by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various anti-bacterial and anti-fungal agents, for example parabens, chlorobutanol, benzoalcohol, phenol, sorbic acid, thimerosal, and the like. In many oases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the principal active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingredients enumerated - 6 above, as required, followed by filtered sterilisation. Generally, dispersions are prepared by incorporating the various sterilised active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.

Ih the ease of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The powders can also be sterilised by use of a gas, for example, ethylene oxide and subsequently incorporating, with the required additional ingredients and in the proper particle size, into the basic powder for later reconstitution with the desired suspending liquid which, of course, itself must be sterile.

As used herein, pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents and the like.

The use of such media and agents for pharmaceutically active substances, is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the present compositions is contemplated within the scope of the Invention, Supplementary active ingredients can also be incorporated into the inventive compositions.

It is especially advantageous to formulate inventive compositions in dosage unit form for ease - 7 of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discreet units suited as unitary dosages for the animal and human subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification, these being features of the present invention.

The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated? the particular condition and its severity? particular form of the active ingredient and the route of administration. A daily dose of from about 1 to about 100 mg/kg, given singly or in divided doses of up to 5 times a day, embraces the effective range for the treatment of most conditions for which the compound is effective and substantially non-toxic. For a 75 kg subject, this translates into between about 75 and about 7500 mg/day. If the dosage is divided, for example, into 3 individual dosages, these will range from about 25 to about 2500 mg of the active ingredient. The preferred range is from about 2 to about 50 mg/kg of ί _ r-* rt I 4»bSo - 8 body weight/day with about 2 to about 30 mg/kg/day being more preferred.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed.

A unit dosage form can, for example, contain the principal active ingredient in amounts ranging from about 0.1 to about 400 mg, with from 1 to about 30 mg being preferred.

Ejipressed in proportions, the active ingredient is generally present in from about 0.1 to about 400 mg/ml of carrier.

In the case Of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

Regression and palliation of cancers are attained, for example, using intraperitoneal administration.

A single intravenous dosage or repeated daily dosages can be administered. Daily dosages up to about 5 to 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to aid regression and palliation of the leukaemia or the like, in the absence of excessive deleterious side effects of a cytotoxic nature to the hosts harbouring the cancer.

In the following date using mice and the base of the above formula where R is ethyl, it can be seen that some toxicity exists at about 50 mgAg and that increasing toxicity occurs from 50 to about 100 mgAg· - 9 45653 Nevertheless, daily dosages up to-about 100 mg/kg are within the preferred range, especially when administered on different regimens and for various of the anthraquinone compounds and salts within the scope of the present invention.

As used herein, by cancer is meant blood malignancies such as leukemia, as well as other solid and non-solid malignancies such as the melancarcinomas, lung carcinomas and mammary tumours. By regression and palliation is meant arresting or retarding the growth of the tumour or other manifestation of the disease compared to the course of the disease in the absence of treatment. In many of the following Examples, mice are used as standard test animals to show the effec15 tive and toxic levels of the novel compositions. It is within the scope of the present invention, however, to treat higher mammals including humans with the novel composition to aid in the amelioration and regression of cancer diseases. Prom the test data with lower mammals it would be expected that the novel compositions are so effective below substantially toxic levels.

The following Examples set forth the manner and process of making and using the inventive compositions. They also include test data showing the effectiveness of the present compositions in treating leukemia-like tumours in standard test animals.

Example 1 - Preparation of Base 121 grams of para leuco quinizarine, or 2,3dihydro-l,4-dihydroxy anthraquinone, were charged with 300 cc of ethyl alcohol solvent into a 1 litre flask.

The mixture was agitated to form a uniform slurry, and to the slurry was charged 124 grams of N-aminoethyl- 10 ethanolamine. The resulting mixture was agitated at room temperature for one hour, heated to 75-80°C and held at that temperature for six hours. While the temperature was maintained at 75-80°C, the mixture was aerated until the leuco product was oxidised as indicated by the product being completely in solution. The solution was cooled to 1O°C, filtered, washed with ethyl alcohol and dried under vacuum. The yield was 138 grams.

Other bases within the scope of this invention can be made with N-aminoethylethanolamine replaced by N-aminomethylmethanolamine, N-aminopropylpropanolamine or N-aminobutylbutanol-amine.

Example 2 - Preparation of Salts Any of the bases of Example 1 can be neutralised with an acid such as acetic or hydrochloric acid to form a salt. An excess of dilute aqueous acetic acid is added to the dried compound of Example 1 (derived from N-aminoethylethanolamine). The mixture is heated to about 50°C ahd held there for about 2 hours. An excess of chloroform is added and after phase separation, the organic phase is discarded. The salt is then vacuum dried.

Example 3 - Preparation of Injectable Composition Ten grams of the acetate salt of Example 2 are dissolved in one litre of saline solution creating a solution with 10 mg/ml of active ingredient. A five ml dose of this composition thus provides 50 mg of active ingredient.

Solutions can be prepared of the various bases and salts of the invention with most standard - 11 45653 pharmaceutically-acceptable solvents. Particularly with the free bases, a surfactant such as hydroxypropylcellulose improves solubility.

Example 4 - Preparation of Powder Composition Ten grams of the free base of Example 1, prepared using N-aminoethylethanolamine is dispersed in 190 grams of glycerine. A one gram dose of this powder thus provides 50 mg of active ingredient.

Powders may be prepared with most standard pharmaceutically-acceptable dispersion agents. The powder may then be combined with other agents as desired and encapsulated by conventional techniques.

Example 5 Six male mice of strain CDF^ were injected on day 0 intraperitoneally with 10θ cells of L-1210 lymphoid leukemia. Beginning on day 1 and daily for a total of 9 days, each mouse was treated by an intraperitoneal injection of 250 mg/kg of body weight of the compound of Example 1 in a carrier of hydroxypropylcellulose sold under the Registered Trade Mark Kluoel. After five days two of the six have survived. The mean survival time was 6.5 days for the test animals, 9.9 days for the controls.

Examples 6 to 11 The test of Example 5 was repeated for groups Of six mice and a group of controls at the doses indicated in Table 1. The mean survival times are indicated in Table 1. The test was discontinued after 30 days. 653 - 12 Table 1 - Lymphoid' Leukemia (L-1210) Example Dose mg/kg Body Weight Survival at 5 Days Mean Survival Time Apparent Cures / 5 250 2/6 6.5 6 125 4/6 6.8 7 62.5 5/6 21.8 2 Control 0 9.9 8 / 95.0 6/6 7.3 9 / 62.5 6/6 11.3 10 / 42.0 6/6 11.3 11 / 28.0 6/6 18.3 2 Control 0 8.4 / Mouse strain BDF^.

/ Mice surviving until end of test.

It appears from these tests that dosages of 62.5 mg/kg of body weight and over begin to show some toxicity to mice under this test regime. Substantially improved survival times compared to the controls (inoculated only) is found in dosages from about 28 to about 62.5 mg/kg of body weight.

Example 12 Six male mice, strain DFC^, were inoculated with P388 lymphocytic leukemia applied intraperitoneally at 10θ cells in ascetic fluid. Beginning the first day after inoculation and then daily for nine days, the compound of Example 1 was applied at a dose level of 128 mg/kg of body weight in saline solution with - 13 43653 Tween 80. Four of six mice survived after five days and the median survival time for the six mice was 5.9 days.

Examples 13 to 29 Example 12 was repeated with groups of six mice at different dosage levels with the results shown in Table 2. This test was discontinued after 30 days.

Table 2 - Lymphocytic Leukemia (P388) Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 12 128 4/6 5.9 13 64 6/6 6.4 14 32 6/6 8.8 15 16.0 6/6 29.7 3 16 8.0 6/6 29.9 4 17 4.0 6/6 29.7 3 Control 0 10.8 18 128 6/6 6.4 19 64 4/6 6.3 20 32 6/6 7.8 21 16.0 6/6 10.1 22 8.0 6/6 21.0 % 23 4.0 6/6 29.7 3 Control 0 11.0 - 14 Table 2 - Lymphocytic Leukemia (P388) cont. 24 128 2/6 5.0 25 64 6/6 6.2 26 32 5/6 8.0 5 27 16.0 6/6 28.8 2 28 8.0 6/6 23.0 29 4.0 6/6 19.8 Control 0 10.8 NOTE: The figure in this and subsequent Tables 10 indicates that the only surviving animals were adjudged upon autopsy to be no -takes for the tumour.

These tests show . substantial activity in the 4.0-16.0 mg/kg body weight range. At a dosage of 32.0 mg/kg and especially 64.0 mg/kg, the toxicity of the drug appears to overtake the beneficial effects.

Sxample 30 Ten more male mice, strain BDP^, were inoculated intraperitoneally with an unspecified level of the homogenate of tumour B-16 melancarcinoma. Beginning the first day after inoculation and every second day thereafter, the mice were treated with intraperitoneal injections Of 128 mg/kg of body weight of the compound of Example 1 in saline solution with Tween-80. Injections occurred intraperitoneally on survivors on days 3, 5, 7, 9, 11, 13, 15 and 17. The median survival time was 5.2 days compared to 21.3 days for the control. Evaluation ended on the 60th day. 43653 - 15 Examples 31 to 47 Example 30 was repeated at dosage levels shown in Table 3 with the results indicated in Table 3.

Table 3 - Melancarcinoma (B-16) Example Dose mgAg Body- Weight Survival at 5 days Mean Survival Time Apparent Cures 30 128 3/10 5.2 31 64.0 8/10 6.1 32 32.0 10/10 10.8 33 16.0 10/10 59.8 8 34 8.0 10/10 59.8 6 35 4.0 10/10 59.8 6 Control 0 21.3 36 128 4/10 5.4 37 64.0 8/10 7.1 38 32.0 10/10 11.1 39 16.0 10/10 51.0 tumoured survivors only 40 8.0 10/10 60.0 10 41 4.0 10/10 43.0 % Control 0 25.3 42 128 10/10 9.3 43 64.0 8/10 16.8 44 32.0 10/10 37.0 45 16.0 10/10 34.0 46 8.0 10/10 36.0 47 4.0 10/10 32.0 Control 0 18.8 Table 3 - Melancarcinoma (B-16) cont.

Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 48 / 128 7.0 49 / 64.0 12.0 50 / 32.0 31.0 51 / 16.0 31.0 52 / 8.0 26.3 1 53 / 4.0 27.0 Control 0 30.3 / The serum of Examples 30 to 41 was diluted 10:1 before inoculation in Examples 42 to 53. Also the surfactant Tween-80 was omitted.

/ In Examples 48 to 53, the injections were on days 1, 3, 5, 7, 9, 11, 13, 15 and 17.

Example 54 Six male mice, strain CDF , were inoculated intra6 peritoneally with 10 cells of L-1210 lymphoid leukemia. Beginning on the first day after inoculation and daily for a total of nine days, the mice were inoculated with intraperitoneal injections of 128 mg/kg of body weight of the compound of Example 1 in saline. Five of the six mice survived to the fifth day and the median survival time was 6.1 days. The test was terminated after 30 days. - 17 Examples 55 to 57 Example 54 was repeated at the dosage levels indicated in Table 4. In Examples 62 to 69 the injections were subcutaneous. In Examples 70 to 77 the oompound was given orally.

Table 4 - Lymphoid Leukemia (L-1210) Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 54 IP 128 5/6 6.1 55 64.0 6/6 7.8 56 32.0 6/6 11.0 57 16.0 6/6 15.3 % 58 8.0 6/6 16.0 59 4.0 6/6 12.8 3 60 2.0 6/6 12.7 61 1.0 6/6 11.3 62 SC 128 6/6 10.3 3 63 64.0 6/6 11.8 64 32.0 6/6 11.8 65 16.0 6/6 10.4 66 8.0 6/6 8.4 % 67 4.0 6/6 8.3 3 68 2.0 6/6 8.4 69 1.0 6/6 8.2 70 Oral 512 6/6 8.1 71 256 6/6 9.0 72 128 6/6 8.8 73 64.0 6/6 8.8 Table 4 - Lymphoid Leukemia (L-1210) cont. Example Dose mgAg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 74 32.0 6/6 8.4 75 16.0 6/6 8.4 76 8.0 6/6 9.2 77 4.0 6/6 9.2 Control 0 8.0 When given intraperitoneally, the compound showed substantial activity at dosages of 16,0 and 8.0 mgAg of body weight. More limited activity was seen in this particular test series when the same or higher dosages were injected subcutaneously or were introduced by oral administration.

Example 78 Ten male mice, strain BDF^, were inoculated with Lewis lung carcinoma homogenate at unspecified dosage intravenously. Beginning on the first day after inoculation and for a total of nine days, the mice were treated with 32 mg of the compound of Example 1 per kg of body weight. After five days all 10 mice survived. The median survival time was 8.2 days.

Examples 79 to 89 Example 78 was repeated at the dosage levels shown in Table 5. In Examples 84 to 89, tumour fragments rather than tumour homogenate were used for inoculation. These tests were discontinued after 60 days. - 19 45653 Table 5 - Lewis Lung Carcinoma Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 78 32.0 10/10 8.2 79 16.0 10/10 18.0 80 8.0 10/10 32.0 % 81 4.0 10/10 23.3 % 82 2.0 10/10 25.0 % 83 1.0 10/10 22.8 Control 0 22.7 84 32.0 10/10 8.4 85 16.0 10/10 11.0 86 8.0 10/10 28.0 87 4.0 10/10 27.0 88 2.0 10/10 39.0 89 1.0 10/10 50.3 Control 0 24.0 For this tumour, the ι effect was appreciably over the dosage range of 2.0- 8.0 mg/kg although the results are not i as dramatic as for other tumour s. The high value in Example 89 is somewhat inconsistent with the toxicity pattern based on body weight change, whioh peaks at a dosage of 2.0 mg/kg· Example 90 Six female mice, strain CDP1, were inoculated 6 intraperitoneally with 10 cells of P388 lymphocytic leukemia. On the first day after inoculation and on days 5 and 9 for a total of three days, the mice were - 20 treated with 512 mg/kg of body weight of the compound of Example 1 in saline solution with Tween-80 surfactant. Tests were discontinued after 30 days. The median survival time was 2.1 days.

Examples 91 to 102 Example 90 was repeated at the dosage levels indicated in Table 6 with the results indicated.

Table 6 - Female Mice Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 90 / 512 0/6 2.1 91 / 256 0/6 2.7 15 92 / 128 2/6 5.0 93 / 64.0 5/6 7.8 94 / 32.0 6/6 29.7 1 95 / 16.0 6/6 26.0 1 Control 0 11.1 20 96 / 64.0 4/6 6.3 97 / 32.0 6/6 8.7 98 / 16.0 6/6 34.9 4 99 / 8.0 6/6 28.0 1 100 / 4.0 6/6 22.3 25 101 / 2.0 6/6 24.0 102 / 1.0 5/6 17.9 Control 0 10.5 / Examples 90 to 95 involved injection on days 1, 5 and 9 only.

/ Examples 96 to 102 and their control were continued to the thirty-fifth day. injections were daily for nine days. - 21 456S3 These tests show substantial activity, particularly at dosages of about 16.0 mg/kg.

Example 103 Ten male mice, strain BDP^, were inoculated with the same unspecified amount of B16 melancarcinoma tumour homogenate as in Examples 30 to 41, diluted 1:10 as in Examples 42 to 53, intraperitoneally. Beginning on the first day after inoculation, and every other day thereafter for a total of nine injections, the mice were injected with 125 mg/kg of body weight of the compound of Example 1 in saline solution with hydroxypropylcellulose, sold as Kluoel. All ten mice survived after 5 days. The median survival time was 8.4 days. The test was discontinued after sixty days.

Examples 104 to 104 Example 103 was repeated at the doses indicated in Table 7.

Table 7 Example Dose mg/kg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 103 125 10/10 8.4 104 62.5 10/10 16.0 2 105 31.2 10/10 49.0 2 106 16.6 10/10 43.3 2 107 8.3 10/10 42.8 Control 0 18.7 6 5 3 - 22 In these tests, substantial results were shown over the dosage range of 8.3-31.2 mgAg- These results further support the activity against melancarcinoma shown in Examples 30 to 53.

Example 108 Ten male mice, strain CDF^, were inoculated with a dilute homogenate of Colon 26 tumour (National Cancer Institute identification C6). They were then injected with 125 mgAg of body weight of the compound of Example 1 in hydroxypropylcellulose solution, sold as Klucel, on days 1, 5 and 9 after inoculation. This evaluation was continued for 70 days. All ten mice survived the fifth day and the median survival time was 27.0 days compared to 26.5 for the controls.

Examples 109 to 112 Example 108 was repeated at the dosages shown in Table 8.

Table 8 - Tumour C6 Example Dose mgAg Body Weight Survival at 5 days Mean Survival Time Apparent Cures 108 125 10/10 27,0 109 35.2 10/10 32.0 110 31.2 10/10 29.0 111 16.6 10/10 29.0 112 8.3 10/10 33.8 Control 0 26.5 - 23 These tests show some effectiveness against this particular tumour. A lesser degree of toxicity was found at the 125 mg/kg level compared to some of the other Examples.

Example 113 Ten male mice, strain CD8F^, were inoculated with CD8P1 mammary tumour homogenate between about 500 to 1000 mg in size, subcutaneously. On days 1, 8, 15 and 22 after inoculation, the mice were treated with an injection of 125 mg/kg of body weight of the compound of Example 1 in hydroxypropylcellulose (Kluoel) intraperitoneally. Eight of ten mice survived the fifth day. After 36 days, the mice were killed and the mean tumour weight was determined to be 630 mg.

Examples 114 to 117 Example 113 was repeated at the dosages shown in Table 8.

Table 9 - Mammary Tumour CD8F^ - Tumour Weight Example Dose mgAg Body Weight Survival at 5 days Mean Tumour Weight (mg) 113 125 8/10 630 114 62.5 9/10 989 25 115 31.2 10/10 423 116 16.6 10/10 1354 117 8.3 10/10 1002 Control 0 1665 6 5 3 - 24 These results indicate substantial inhibition of tumour growth at many levels and apparent decreases in tumour sizes in some instances.

The surface active agent referred to in this specification under the Registered Trade Mark TWEEN 80, is a mixture of polyoxyethylene ethers of a mixture of Oleyl partial esters of sorbitol anhydrides.

Claims (12)

1. CLAIMS ; 1. A composition for aiding regression or palliation of cancer in mammals which comprises as active ingredient an anthraquinone compound of the formula; where R is alkylene having 1 to 4 oarbon atoms, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

2. The composition of claim 1 where R is ethylene.

3. The composition of claim 1 wherein the active ingredient is said anthraquinone compound as a free base.

4. The composition of claim 1 wherein the active ingredient is a pharmaceutically acceptable salt of said anthraquinone compound.

5. The composition of claim 4 wherein the active ingredient is an acetate salt of said compound.

6. The composition of claim 1 wherein the active ingredient is present at between about 0.1 and about 400 milligrams per millilitre of carrier.

7. A composition according to claim 1 substantially as herein described.

8. Por use in the treatment of the human body for therapy of cancer, an anthraquinine of formulas .y - 26 43653 NH-R-NH-ROH NH-R-NH-ROH wherein R is an alkylene group having 1 to 4 carbon atoms.

9. The anthraquinone of formula 1, for anti-cancer use, wherein R is ethylene. 5

10. Pharmaceutically acceptable salts of the compounds defined in claim 8 or 9.

11. Salts according to claim 10 which are the monoacetate or diacetate.

12. An anthraquinone or pharmaceutically acceptable 10 salt thereof, as claimed in claim 8, 9, 10 or 11, for use in the treatment of the human body for therapy of leukaemia.