Dr. P.M. Dewick. Tumor Inhibitors from Plants, in Treaseand Evans' Pharmacognosy (13th. ed.) 1989, W.C. Evans, BaillièreTindall, London

Comprehensive technical overviews of this whole field can be found in :

Pettit et.al., (1977 - 1985). Biosynthetic Products for Cancer Chemotherapy;Vols. 1-3 New York: Plenum Press; Vols. 4-5 Elsevier, Amsterdam

Cassady and Douros (Eds.), (1980). Anticancer Agents based on Natural Product Models.
Academic Press, New York

The orthodox chemo therapeutic approach to cancer is based upon drugs that inhibit the characteristically uncontrolled development of abnormal cells. This is done by either inhibiting cell division or by killing the cells. Many of the chemicals used are based upon chemical warfare agents such as nitrogen mustard gas. It was discovered that when used in a controlled therapeutic way the toxicity could be directed to some degree. From a pharmacological perspective, an `ideal' chemo therapeutic drug would kill the cancer cells without damaging normal cells. Drugs based upon the chemical attack of alkylating agents such as nitrogen mustard have not proved all that successful in being both effective against cancer cells whilst harmless to others. There area plethora of ethical issues here. Whilst this course is not the place to explore them, please give this some thought.

Research is focusing on the search for new molecular prototypes, new types of chemo therapeutic agent, and plant medicines are proving to be excellent sources of these new compounds. Whilst herbalist's know well that plants have much to offer in the treatment of cancer, it is coming as a surprise to researchers that our `weeds' have such virtues. A recent survey lists over 1400 genera of herbs that have a history of use in cancer treatments.<sup>1, 2

1</sup> Hartwell, J.L. : `Plants used against Cancer. A survey.' Lloydia 30, 379-436 (1967) <sup>2</sup> Hartwell, J.L. : `Plants used against Cancer. A survey.' Lloydia 32, 204-255 (1971) Phytopharmacological research is showing a chemical basis for the reputation of well known anti-cancer remedies, as well as suggesting possibilities in `new' plants.³This search for novel anti-cancer drugs is paradoxically producing excellent scientific information on many previously unresearched herbal remedies.

Recent phytochemical examination of plants which have a suitable history of use in folklore for the treatment of cancer has often resulted in the isolation of principles with antitumor activity. Podophyllum was used this way over 2000 years ago by the Chinese, and resins from Podophyllumhexandrum and the May-apple (P. peltatum) contain lignans having antitumor activity. Whilst the major constituent, podophyllo toxin, are unsuitable for use two derivatives, etoposide and teniposide, have given good results in clinical trials. Etoposide is available for the treatment of small-cell lung cancer and testicular cancer, and teniposide is used in pediatric cancers.

Since antiquity the juice of Bittersweet (Solanum dulcamara) has been used to treat cancers, tumors and warts, and references to its use have appeared in the literature of many countries. A tumor-inhibitory constituent has been identified, the steroidal alkaloid glycoside [[beta]]-solamarine. Lichens, e.g. species of Cetraria and Usnea, also have a history of use in folk medicine against cancer. These are all rich sources of usneic acid, well known as being antibacterial and anti-fungal, but only recently as anti-tumor. The druids used Mistletoe (Viscum album) to treat cancer, and research has found marked anti-tumor activity with fractions of Mistletoe extract.

The most important plant source of materials used in chemotherapy are the alkaloids of Madagascar Periwinkle (Catharanthus roseus). Research was stimulated by its traditional use in the treatment of diabetes. No hypoglycaemic activity was detected, but the susceptibility to bacterial infection in the treated test animals led the researchers to look for possible immunosuppressive effects. Alkaloids with anti-leukemic activity were found, and vincaleukoblastine(vinblastine) and leurocristine (vincristine), are now used, either alone, or in combination with other forms of therapy for cancer treatment. Difference sexists in the kinds of tumors which respond to these alkaloids. Vinblastineis mainly useful in the treatment of Hodgkin's disease, a cancer affecting the lymph glands, spleen and liver, whilst vincristine is used for childhood leukemia. For more details please refer to :

Taylor, W.I. and Farnsworth N.R. (1975). The Catharanthus Alkaloids.Marcel Dekker, London

Methods of investigation
Of the world wide efforts being made, perhaps the best known is that of the US National Cancer Institute. The program aims to screen all the flowering plants of the world to identify anti-tumor activity, a major undertaking! A random-selection screening program was adopted. Since the beginning of the program, a vast number of extracts from sources has been tested for anti-tumor activity. About 4% of the extracts have shown reproducible activity. Over about 25 years, some 114, 000 plants representing 40, 000 species have been tested. Different parts of a plant leaves, roots, etc.--are separately examined wherever possible.⁴ In other words, many hundreds of potentially useful chemicals have been found so far, even with under 10% of the plants yet examined. This begs the question of the validity of using the plants themselves, as the research does not examine the use of the whole plant on human cancers.

A brief review of techniques used is illuminating. The thorny ethical issues will not be emphasized here, but should be obvious to all herbalist's.

The isolation of biologically-active constituents involves different techniques than ordinary phytochemical evaluation. In these, the focus is often on easily extracted constituents, those in the largest quantities or which crystallized readily, or those which are the researcher's field of interest, e.g. alkaloids, terpenoids, phenols, etc. Identification of biological activity was secondary to elucidation of their chemistry, and thus testing for such actions would depend on sufficient material being available. Many medicinally useful compounds have been missed in this way. Current procedures examine the biological activity of all parts of the plant and each fraction of the extract before any constituent is isolated. Usually only those fractions showing biological activity are studied further.

Such changes in approach reflect the recognition by pharmacologists that such activity is a complex process, leading some theorists to sound like medical herbalist's! It is well known that isolated constituents of a plant drug may not give the same clinical response as a preparation of

³ Casually & Douros (1980). Anticancer Agents Based on Natural Product Models. New York: Academic Press.

⁴ Cordell, G.A . : Anti-cancer agents from plants., Progr.Phytochem., 5, 273

that plant. Often, the total therapeutic activity is greater than, or different from the therapeutic activities of the individual chemicals. Synergism or antagonism due to the complex nature of the extract has been postulated as an explanation. It is common for a fraction from a plant extract that has significant biological activity, to contains no single constituent with this activity.

• Routine testing of extract fractions is usually done via an in vitrocytotoxicity test. Such tests are not always a reliable means of predictingin vivo antitumor activity, but they are quick and inexpensive.
• Initially solvents are used to remove much of the inactive material.
• A range of chromatography techniques are then applied for more refined separation of constituents. This is a highly skilled process, needing to avoid chemical changes and separate very similar molecules.
• The chemical structure of the compounds is determined by reviewing spectrographic findings together with phytochemical and biosynthetic reasoning. X-ray crystallography is often employed to establish a definitive structure.
• Promising chemicals are then tested on cancer tissue which have been developed to standardize experimental findings.
• If these results are encouraging, the next stage is pre-clinical toxicological studies.
• This requires relatively large amounts of material, larger-scale extractions and fractionation facilities.