WO2009141645A1

WO2009141645A1 - Cancer therapy

Info

Publication number: WO2009141645A1
Application number: PCT/GB2009/050534
Authority: WO
Inventors: Max Reynolds
Original assignee: Max Reynolds
Priority date: 2008-05-19
Filing date: 2009-05-19
Publication date: 2009-11-26
Also published as: GB0809046D0

Abstract

The present invention relates to the use of a non-monoterpenoid compound derived from Melaleuca plant for the treatment or prophylaxis of cancer. In particular, the present invention relates to a composition derived from Melaleuca Alternifolia comprising enhanced levels of sesquiterpenes for the treatment or prophylaxis of cancer.

Description

CANCER THERAPY

FIELD OF THE INVENTION

The present invention relates to agents and methods for use in cancer therapy. In particular, the invention relates to the use of non-monoterpenoid compounds derived from Melaleuca plants and in particular sesquiterpenes and sesquiterpenoids for the treatment or control of cancer.

BACKGROUND OF THE INVENTION Treatment of human cancer is an area of clinical medicine that has and received considerable attention. Conventional cancer treatment methods include chemotherapy, radiation and surgery, each of which has its own disadvantages. The well recognized disadvantage of chemotherapy is its nonselectivity between norma! and cancer ceils. With a view to addressing this problem of non-selectivity, current research is investigating the use of biochemical agents that maybe specific to cancer cells. There are two broad classes of such agents. The first is directed at binding cancer specific receptors on the cell surface. The second type is aimed at the survival and apoptosis pathways.

However, many pathways and proteins control eel! death and survival. This complexity significantly adds to the problems associated with finding an effective agent. Still further, the types of receptors and deregulated pathways are generally cancer dependent. This means that chemotherapeutic agents are cancer specific. For example, is well known that agents useful for treating hormone related cancers such as breast and prostate would be ineffective in controlling other types of cancers such as squamous ceil carcinomas or adenocarcinomas.

To date, there have been many thousands of compounds that have been undergone in vitro testing for the treatment of cancer. Whilst many of these compounds have been shown to have cytotoxic activity against cancer cells in vitro, they have failed to be adopted for cancer treatment. A major reason for such failure is unacceptable toxicity to normal cells and/or side effects. It is cleariy desirable to investigate new anti-cancer agents and therapies that are selective for cancer cells and may also be effective against different forms of cancer.

SUMMARY OF THE INVENTION According to a first broad from of the invention there is provided a method for the treatment or prophylaxis of cancer comprising administering to a patient a therapeutically effective amount of at least one non-monoterpenoid compound found in the oil from a Melalueca plant.

The present invention is based around the surprising and unexpected discovery that a non-monoterpenoid compound found in the oil from Melaleuca plant is able to treat or control cancer, whilst having minimal toxicity. This is to be compared to the teachings of the prior art in which monoterpenes limonene and periliyi alcohol have been reported to have antineoplastic activity. Tea tree oil has been reported to be active against melanoma cells in vitro. The major component of tea tree oil, terpinene-4-ol is considered to be the active ingredient. However, the present inventor believes that the levels of tea tree oil or terpinen-4-ol required to show an effect in vitro when extrapolated to provide a therapeutic dose in a human would be at levels that would exhibit unacceptable toxicity.

According to another broad form of the invention, there is provided a use of a non- monoterpenoid compound found in a Melaleuca plant for the treatment of cancer.

There is also provided use of non-monoterpenoid compound found in a Melaleuca plant for the production of a medicament for the treatment of cancer.

Definitions

The term "monoterpenoid" refers to a monoterpene-like substance and may be used loosely herein to refer collectively to monoterpenoid derivatives as well as monoterpenoid analogs. Monoterpenes are derived from an isoprene unit and have the formula CioHie. Monoterpenoids can therefore include monoterpenes, alcohols, ketones, aldehydes, esters, ethers, acids, hydrocarbons without an oxygen functional group, and so forth. !t is common practice to refer to certain phenolic compounds, such as eugenol, thymol and carvacroi, as monoterpenoids because their function is essentially the same as a monoterpenoid. Although, these compounds are not technically "monoterpenoids" (or "monoterpenes") because they are not synthesized by the same isoprene biosynthesis pathway, but rather by production of phenols from tyrosine common practice will be followed herein.

The term "sesquiterpene" as used herein refers to a compound having a 15-carbon skeleton with non-linear branches. The molecular formula is Ci5H₂4- The term "sesquiterpenoid" refers to a sesquiterpene-like substance and may be used loosely herein to refer collectively to sesquiterpenoid derivatives as well as sesquiterpenoid analogs. Sesquiterpenoids can include sesquiterpenes, alcohols, ketones, aldehydes, ethers, acids, hydrocarbons without an oxygen functional group, and so forth.

The levels of monoterpenes present in the tea tree or Melaleuca Alternifolia oil are governed by International and Australian standards. The % min and % max for the Australia Standard, typical composition and a preferred composition as described below are shown in the following Table 1.

It may be seen that the minimum level of monoterpenes is 17% and the maximum sesquiterpene level is 19.5%. Typical levels are 37.1% monoterpenes and 3.9% sesquiterpenes. The levels in the preferred embodiment are 1.15 % monoterpenes and 13.8% sesquiterpenes. In may be seen that the composition of the preferred embodiment contains a significantly different monoterpene/sesquϊterpene profile than that of typical oil. The terpinen-4-ol levels are similar. Whilst not wishing to be bound by theory, the present inventor believes that such a level of terpinen-4-ol is tolerable, as will be illustrated in the examples that follow.

Although some compounds may be found in the Melaleuca plant as a single or predominately one isomer, the compounds suitable for use in the invention are not necessarily limited to that isomer and may also include other isomers or a mixture thereof.

The term "oil from a Melaleuca plant" refers to oil that may be obtained from the leaves and branchiets of a plant of the Melaleuca genus. Plant oiis, commonly referred to as "essential oils" are conventionally obtained by steam distillation. However, for the purposes of the present invention, the compounds may be obtainable by any suitable method including solvent extraction.

The term "found in the oil" simply means that the compounds are those found in the oii from a Melaleuca plant but does not limit the compounds to being obtained from plants of the Melaleuca genus. The compounds may be sourced from other plants and may also be synthesized.

The term "treatment of cancer" means the inhibition, control or any other adverse effect on cancer cell growth. It may also include induced apoptosis of cancer cells.

The term "prophylaxis of cancer" means an anti carcinogenic effect against the onset of cancer or against the relapse of cancer. As the compositions used in the methods of the present invention have low or negligible toxicity, long term use at low or preventative levels should cause little or no harm to a patient. This may be compared to conventiona! chemotherapeutic agents whereby long-term use would cause harmful side effects.

The term "patient" as used in this application refers to any mammal, preferably humans.

Cancers suitable for treatment by the method of the present invention include but not limited to breast cancer, lymphatic cancer, lung cancer, stomach cancer, cervical cancer, prostate cancer, colon cancer and melanoma.

The compounds of the present invention may also be used as part of a combination therapy with other agents or as an adjunct therapy in radiation therapy. It is believed that the compounds of the invention may be able to sensitize cancer cells to action by other antineoplastic agents or radiation therapy.

The instant invention also provides for compositions which may be prepared by mixing one or more non-monoterpenoid compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like. The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art such as conventional mixing, dissolving, encapsulating, lyophilizing or emulsifying, among others. The compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pilis, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive. Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitoi, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, coHagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyi-cellulose, and/or polyvinylpyrrolidone. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments may be added for identification. Tablets and pills may be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. For nasal or buccal administration, the pharmaceutical formulations may be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. The compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or triglycerides.

For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.

For rectal administration, the pharmaceutical formulations may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.

The compounds may also be administered dermally. It has been observed that the compounds are readily absorbed through the skin such that dermal uptake directly into the lymphatic system by dermal application about the lymph nodes is possible. Dermal administration may be by any suitable form as such as in the form of a topical gel/ointment and the like or a dermal patch.

Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention.

The compound or compounds for use in the method of the present invention may be administered in an essentially pure form, although this is not necessary. The compounds may be obtained from the oil of a Melaluca plant from the oils of other plants or may be synthesized. The plant oils may be obtained by any suitable technique such as steam distillation, super critical fluid extraction and solvent extraction. The compounds may be fractionated by any suitable technique and such methods are well known in the natural product chemistry art. One suitable technique is that of separation on a silica gel column or by thin layer chromatography.

In one form of preparation, the at least one compounds may be in the form of an oil fraction containing an enhanced level of non-monoterpenoid compounds. By enhanced, it is meant that the concentration of non-monoterpenoid is higher than that normally found in the source oil fraction. Jt will be appreciated by those of skill in the art that the levels of components in natural pant derived soils can vary with seasons, age of the plant, variety of the plant and the like. However, there is generally an accepted range for such oils (as reflected in the above standard), such that enhanced would be understood to be outside the normal phytochemica! variations.

it will be appreciated that when derived from a natural oil, the compounds or composition as used in the invention may tolerate some levels of monoterpeπoid compounds, provided that the levels of monoterpenoids do not dilute the non- monoterpenoϊds to an insufficiently low therapeutic level and/or present an undesirable level of toxicity.

Suitable dosage ranges of the at least one compound are between about 10mg to about SOOmg, typically between about 10mg to about 200mg and preferably between about 10mg to 150rng per day for a 70kg human. Where the compounds are found in oil that may contain tolerable levels of monoterpenoid compounds, the dose of the total oil may be between about 100mg to about 900mg, preferably between about 150 to about 400mg and most preferably between about 150mg to about 300mg per day for a 70kg human.

The major non-monoterpenoid constituents of the oil found in a Melaleuca plant are sesquiterpenoids. Sesquiterpenoids are classified into groups according to their skeletal structure. Classes of sesquiterpenes that may be found in Melaleuca plants include the cadinenes (1) guaienes (2) cubebenes (3) aromadendrenes, (4) panasinsenes (5), caryophillenes (6), himachalenes (7), elemenes (8), patchoulenes (9) eremphilenes (10), copaenes (11), farnesenes (12), longifolenes (13), germacrenes (14), aristolenes (15) and humulenes (16).

(D (2)

(16)

Especially preferred are the cyciic sesquiterpenes, and in particular the dicylcic and tricylic sesquiterpenes as found in Melaleuca Aiternifolia.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the relationship between cancer ceil population and oil concentration;

Figure 2 is an SEM micrograph of normal HeIa cells;

Figure 3 is an SEM micrograph of HeIa to which 0.001% oil has been added;

Figure 4 is an SEM micrograph of Heia to which 0.003% oil has been added; Figure 5 is an SEM micrograph of HeIa to which 0.006% oil has been added;

Figure 6 is an SEM micrograph of HeIa to which 0.008% oi! has been added;

Figure 7 is an SEM micrograph of HeIa to which 0. 1 % oii has been added and

Figure 8 is an SEM micrograph of HeIa to which 0.2% oil has been added. DETAILED DESCRIPTION OF THE INVENTION

Oil from Melaleuca alternifolia was treated to remove essentially all the monoterpene content by elution through a silica gel column. The remaining fraction was analysed by GCMS with reference to the NIST98.L library. The fraction contained the components shown in Table 2.

TABLE 2

In some cases, it was not possible to make an unambiguous identification of compounds, in this case, all compounds matched by the database and respective qualifiers have been included in the Table. However, it will be noted that, in most cases, even where there may be a possibility of different structures, that in the cases of sesquiterpenoids, the possible alternatives may be isomers or have an otherwise closely related chemical structure.

It may be seen that the monoterpene level is very low at about 1.96% and that the sesquiterpene content is much higher, at about 34%, than compared with conventional tea tree oil.

it will be appreciated that for the reason given above, there may be photochemical variations in the composition of the source plant that may translate into the final composition. Photochemicai variation is considered tolerable and the typical dosages as discussed and exemplified therein would accommodate such phytochemica! variation. Toxicity Studies

A 10% aqueous solution of the tea tree extract was prepared and rat toxicity tests were conducted. The LD_5D was calculated to be 21g/kg bw of male wistar rats. This is essentially a non-toxic compound. When this value is converted to human (70)kg using a body surface area method, then the oral dose of 208.87g (2.98g/kg man) is found.

In vitro trials Human mammary carcinoma MCF-7 cells

Samples of healthy growing human mammary carcinoma MCF-7 cells were established in 96 well microtitre culture plates in full RPMI or DMEM growth media containing 10% Fetal Calf Serum. The cells were initially established at ca 10,000 cells per well for 1 day assays and ca 5,000 cells per well for the 3 day assays. Some columns of wells in the plate were kept as controls containing media alone. Stock solutions of the oil extract at 1 to 9 parts dissolved in either neat ethanoi or DMSO were prepared to enable the oil to solubilise in the media. Serial dilutions were then prepared using complete culture media as diluents across the columns of the plate. Either 4 or 10 fold dilution series were used as indicated. The plates of cells were then returned to the 37 degree CO₂Jncubator for a period of either overnight or 3 days. After treatment with the oil, a metabolic indicator dye (XTT) was added into each well and the plates incubated to allow the dye to develop for a further period of 1-2 hours. The absorbance at 490nm was measured in a plate spetrophotometric reader and the data analysed. Ail data shown were background subtracted for the absorbance values obtained with XTT dye aione added to media. The final absorbance values were calculated as the percentage live cells relative to the cells not treated with the oil used as controls.

The IC50 values were calculated. IC50 is the concentration of agent that provides a 50% reduction in the growth of treated cells as compared to the untreated cells as control. The results are shown in Table 3 below:

TABLE 3

These results show that the oil is cytotoxic to cancer ceils.

Human Cervical Cancer Cells (HeIa); Human coion Cancer cells (HT29) and Human colon cancer Cells (SpcA-1 ).

Studies were conducted observing the effect of cancer cell concentration on the above three cell lines after treatment with increasing amounts of the composition of the invention. The results are shown in Figurei.

It may be seen that at a concentration of 0.008%, the composition was effective in kiliing ceils of all cancer cell lines. That a single agent shows a similar effect across three distinctly different cell line is surprising. This suggests a non cancer specific mode of action, although showing a selective toxicity to cancer as compared to normal ceils as shown in the toxicity studies.

These results may be compared to those as reported in an article published by Calcabrini et al in The Journal or Investigative Dermatology 3004 p 349 - 360. In this study, the effect of a conventional tea tree oii, having a composition similar to the typical composition referred to in Table 1 above on melanoma cells was studied. A concentration of 0.01% (i.e. higher than 0.008%) showed no effect on the growth of norma! melanoma M14WT cells and decreased the growth (but did not decrease the number) of resistant M14 ADR cell lines. A concentration of 0.03% was required to reach a zero cell number and the time period for this was 8 days for M14WT cells and 3 days for M14 ADR cells.

The present inventor believes that this contrasts significantly to that of the present invention showing a kill concentration of 0.008% after only 1 day for three different cancer celi lines. Further, this prior art teaches that terpinen-4-ol is the active anti- neoplastic agent. Whilst not wishing to be bound by theory, the present inventor believes, that whilst terpine-4-o! may exhibit some effect, the extrapolated therapeutic dose would be unacceptably toxic. The present inventor believes that the non- monoterpenoid compounds, and in particular the sesquiterpenoid fraction is the most active, and ieast toxic. The present inventor believes that the observation that the above trials show a significantly improved anti-neoplastic effect with similar levels of terpinene-4-ol as the prior art shows the activity of the non-monoterpenoid compounds present in the oil composition. Clearly the sesquiterpenoid levels in conventional tee tree oϋ are too low to show any effect in the prior art studies. Electron Microscopy Studies

Figures 2 to 8 show HeIa ceils with the concentrations of the composition of the invention added. In figure 2, typical live cancer cells are indicated by lines A. In figure 3, it can be seen that at 0.001% there is a reduction in cancer cells. There is a steady reduction in cell number with increasing concentrations and no iive cancer cells are visible at 0.008%. Lysed cancer cells may be seen in figure 8 at 0.2% concentration. Ceil nuclei are indicated by lines B.

Antioxidant trial

An ORAC antioxidant study was conducted by Brunswick Laboratory according to the protocol described in Huang et al. "High throughput Quantitation of Peroxyl Radical Scavenging Capacity in Bulk Oils by monitoring Oxygen Consumption Rates", Journal of Agricultural and Food Chemistry 2006, 54, 5299-5305.

The ORAC analysis provides a measure of the scavenging capacity of antioxidants against the peroxyl radical, which is one of the most common reactive species found in the body. Vitamin E is used as the calibration standard and the ORACoil result is expressed as micromole vitamin E equivalent (VE) per litre.

The result for the oil extract as described above as compared to other antioxidants is shown below in Table 4:

TABLE 4

it may be seen that the oil of the invention shows a remarkably high anti-oxidant activity. Whilst not wishing to be bound by theory, the present inventor believes that this high ant-oxidant activity has an anti-carcinogenic effect.

Pharmaceutical compositions

Capsuies were prepared as follows: oi! from Melaleuca 1 50 mg microcrystaliine cellulose 650mg total 800mg

Suppositories were prepared as follows: cocoa butter 70grams soya oi! 5 grams oil from Melaleuca 25 grams

The above mixture makes 1gram suppositories having an oil content of 0.250grams.

Cervicai Cancer

A patient presented with a re-occurrence of cervical cancer. The patient had contracted cervical cancer 3 years previously and had undergone chemo and radiation therapy. The procedure had a number of undesirable side effects that left her with a permanent colostrums bag and rectal ulcers.

The patient experienced a relapse of the cancer. Treatment was begun using the method of the present invention. The patient was administered the extract as described above in relation to Table 1. 150mg was administered orally and 250mg rectaily on a daiiy basis for a period of 2 months. After this time period, there was no longer any evidence of cancerous cells as tested by pap smear and cervical scrap.

Treatment was continued for a further 2 months after which time biood tests were performed. Blood chemistry indicated no evidence of cancer.

Prostate Cancer

A patient was diagnosed with prostate cancer with a PSA reading of 4.2μ (normal range is less than 3.5) with physical examination showing many small cancer growths. His physician had recommended surgery.

The patient was treated with a daily oral dose of 150mg and a daily rectal dose of 250mg. After daily treatment for 60 days, an MRI scan showed no sign of cancer cells in the prostate and the PSA values had dropped from 4.2μg/L to 2.7μg/L Based upon these results, it was decided that surgery was no longer necessary.

Treatment was continued for a further 2 months after which time blood test were performed. Blood chemistry showed the PSA values had dropped to well below 4.2μg/L indicated no cancer activity.

Colon Cancer

A patient presented with colon cancer. The patient's CRP was 19mg/L and she was losing weight. Surgery had been recommended but the patient did not want the surgery.

The patient was treated with a daily oral dose of 150mg and a daily rectal dose of 250mg. After this time, her CRP level had dropped to 8mg/L and her weight had stabilized. Treatment was continued for a further 2 months.

The indications were that the growth of the cancer had been stopped. The patient then agreed to have the surgery performed. The surgeons believe the surgery to be successful.

It may be seen that the method of the present invention was successfui in treating or controlling three very different forms of cancer. That a single agent is successful against different forms of cancer is itself surprising.

None of the patients reported any adverse side effects of the therapy and to the contrary reported an improvement in their genera! well being. Whilst not wishing to be bound by theory, the present inventor is of the view that the composition is effective in stimulating the immune system.

A further advantage of the low or negligible toxicity of the compounds as used in the invention is the safety for those preparing and administering the formulations. The hazards assisted with administrating chemotherapeutic agents are well known. Still further, in many cases, there is a narrow margin between a therapeutic and a toxic dose of chemotherapeutic agents. This would not be the case with the methods of the present invention, thereby adding a further level of safety to the patient and minimization of undesirable side effects.

It may be seen that in the early stages, the method of the present invention may be successful in halting the growth of the cancer, or even removal of the cancer. At later stages of disease, the method may be successfui in controlling the growth of the cancer. The present invention may also be suitable in the treatment of metastatic cancers of unknown primary origin. It is generally necessary to know the nature of a primary cancer, as the treatment depends upon the type of primary cancer. For example, where cancer in the lung is caused by the spread of breast cancer cells, the cancer is not lung cancer but metastatic breast cancer. However, the compositions of the present invention are active against a range of cancer types. It will be appreciated that various changes and modifications may be made to the present invention as described and claimed herein, without departing from the spirit and scope thereof.

Claims

1. Use of at least one πoπ-monoterpenoid compound found in a Melaleuca plant for the treatment or prophlaxis of cancer.

2. Use of at least one non-monoterpenoid compound found in a Melaleuca plant or derivative thereof for the production of a medicament for the treatment or prophylaxis of cancer.

3. The use of claim 2, wherein the medicament is formulated to comprise a daiiy dose of between about 10 to about 500mg, preferably between about 10 to about 200mg, more preferably between about 10 to about 150mg for an adult human.

4. Use of any one or claims 1 to 3, wherein the at least one compound is a sesquiterpenoid.

5. The use of claim 4, wherein the sesquiterpenoid is selected from the group consisting of the cadinenes, guaienes, cubebenes, aromadendrenes, panasinsenes, caryophilfenes, himachaleπes, elemenes, patchoulenes, eremphilenes, copaenes, farnesenes, longifolenes, germacrenes, aristolenes and humuienes.

6. The use of any one of claims 1 to 5, wherein the at least one compound is a non-monoterpenoid compound as listed in Table 2.

7. Use of a composition comprising at least one non-monoterpenoid compound wherein said composition is an oil fraction that has been prepared from oil from a Melaleuca plant treated to remove essentially all the monoterpene fraction, for the treatment or prophylaxis of cancer.

8. The use of claim 7, wherein the Melaleuca plant is Melaleuca Alternifolia.

9. The use of claim 7 or claim 8, wherein said composition is formulated to provide a daily dose of said oil fraction of between about 100 to about 900 rng, preferably between about 150 to about 400mg and most preferably between about 150 to about 300 mg per day for a 70kg human.

10. The use of any one of claims 7 to 9, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, stomach cancer, cervical cancer, prostate cancer, colon cancer and melanoma.

11A method for the treatment or prophylaxis of cancer comprising administering to a patient a therapeutically effective amount of at least one non-monoterpenoid compound found in the oil from a Melalueca plant.

12. The method of claim 11, wherein the at least one compound is administered at a daily dose of between about 10 to about 500mg, preferably between about 10 to about 200mg, more preferably between about 10 to about 150mg for an adult human.

13.A method for the treatment or prophylaxis of cancer comprising administering to a patient a therapeutically effective amount of a composition comprising at least one non-monoterpenoid compound found in the oil from a Melalueca plant.

14. The method of claim 13, wherein said composition is an oi! fraction that has been prepared from oil from a Melaleuca plant treated to remove essentially all the monoterpene fraction, for the treatment or prophylaxis of cancer.

15. The method of any one of claims 11 to 14, wherin the Melaleuca plant is Melaleuca Alternifolia.

16. The method of any one of claims 1 to 15, wherein the at least one compound is a sesquiterpenoid.

17. The method of claim 16, wherein the sesquiterpenoid is selected from the group consisting of the cadinenes, guaienes, cubebenes, aromadendrenes, panasinsenes, caryophiilenes, himachalenes, elemenes, patchouienes, eremphϋenes, copaenes, famesenes, longifolenes, germacrenes, aristolenes and humulenes.

18. The method of claim 11 , wherein the at least one compound is a non- monoterpenotd compound as listed in Table 2.

19. The method of any one of claims 11 to 17, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, stomach cancer, cervical cancer, prostate cancer, colon cancer and melanoma.

20. The method of any one of claims 11 to 19, wherein the at least one compound is administered orally and/or rectally.