Plants & Cancer Research

This section has been written in an attempt to provide an insight for the herbalist about allopathic research and use of plants in oncology. It is by no means comprehensive, and is not meant to imply any endorsement of the techniques or principles. It also is not meant to imply any a prioridisapproval or criticism. Unless otherwise referenced, the information in this section comes from an excellent and eminently readable review :

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.

Few compounds reach clinical trials. A low therapeutic index (the ratio of maximum tolerated dose to minimum effective dose), undesirable side-effects or high toxicity may outweigh beneficial tumor-inhibitory activity. Of 25, 000 screens conducted annually by the NCI (including both synthetic and natural materials), only 8-12 compounds are likely to be selected for pre-clinical testing, and only 6-8 may go on to clinical trials.



The random-selection screening program for natural products was terminated by the NCI in 1983. In over 25 years, the program did not identify a single agent for use in the allopathic treatment of cancer. Nevertheless, the number of cytotoxic and anti-tumor agents identified was enormous. The NCI has certainly not lost confidence in the potential of natural products as leads for new anti-cancer agents. Instead of the random-selection screening program, anew screening system was begun in 1986, reducing the scale of the operation, and concentrating on the less thoroughly investigated groups of organisms, including plants, marine animals, fungi and cyanobacteria.



When found using the approach outlined above, tumor-inhibiting constituents are often new to science, and span a wide range of structure. Occasionally, however, they are well known but had not been screened the correct way. Examples relevant to the phytotherapist include usneic acid (Usnea spp.), ellagic acid (Quercus spp.), the anthraquinone aloe-emodin (Cascarasagrada), juglone (Juglans spp.), pyrrolizidine alkaloids, aristolochicacid (Aristolochia spp.), hellebrigenin (Helleborus niger: Black Hellebore), the well known alkaloids used to treat gout from the Autumn Crocus (Colchicum autumnale) and cucurbitacins found in species of Euphorbia, Hypericum and Ecbalium elaterium (the squirting cucumber).



An interesting finding in such research concerns the controversial pyrrolizidinealkaloids, known for their hepatotoxic properties, especially to grazinganimals. Those found in Senecio spp., however, have shown antitumoractivities at dose levels lower than that which is toxic. Indicine-N-oxidefrom Heliotropium indicum (a botanical relative of Comfrey) showedno marked hepato-toxicity, possessed significant anti-tumor activity, and went to clinical trials. The compound showed substantial activity in acute leukemia, but hepatotoxicity was more severe than expected, and the cause is not known.



Studies around the world have identified many new constituents with anti-tumoractivity, and a number of these have been considered sufficiently active for clinical studies to be commenced. Similarly there is much attention given to possible mechanisms of action. Such considerations go beyond the range of this course (let alone my ability to comprehend). The learned journals abound in papers that address all of these issues, for details please refer to the references given above.