Cancer treatments

  • All anti cancer products originated from plants, the secondary products are what are used 

  • 77 introduced from 80s to 2000

    • 12 biologicals - proteins and peptides 

    • 30 natural secondary products 

    • 18 synthetic mimics 

    • 17 total synthetics 

  • Groups of diseases with common symptoms - malignant cell growth and uncontrolled cell division 

  • Norma cells 

  • Cancerous cells - uncontrolled cell divisions, blood vessel proliferation to feed cancer cells 

  • Cytotoxic drugs - cell killing drugs

    • Prefer cancer cells, attacks cells that rapidly divide 

    • Chemotherapy 

    • Come from secondary products isolated from plants 

    • ….

Rosy periwinkle 

  • Erect annual, native to madagascar, cultivated in warm climates (ornamental but some places a weed)

  • Use in folk medicine - passed down through oral tradition 

    • Madagascar and caribbean - anti-diabetic, insulin substitute 

    • South africa, philippines and southern europe - used to lower blood sugar levels, rheumatism (anti-inflammatory properties)

  • Main use was diabetes 

    • Investigations into properties and how it helps, awareness of it in western medicine 

    • Began testing for anti-cancer properties - was cytotoxic but does not affect all types of cancer (did not test for leukemia, blood cancer)

      • Thought it did not work until robert noble and charles beer discovered that periwinkle extract lower white blood cell count and bone marrow count 

        • Cells come from bone marrow, white blood cells are the cells affected in leukemia 

    • Leukemia 

      • Periwinkle investigation on effects of it

      • Isolation of vinblastine alkaloid 

        • Effective against hodgkin's disease (blood cancer that affects lymphatic system, immune system)

        • Choriocarcinoma - placental cancer, starts as tumor in uterus then into the placental tissues 

        • Neoplasms - tumors, abnormal tissue growth 

      • Vincristine alkaloid 

        • Effective against childhood leukemia 

      • Semi synthetics 

        • Vinorelbine 

          • Vinca alkaloid 

            • Anti-mitotic, effects spindle formation 

          • Effective against breast cancer 


Pacific Yew 

  • Tree, native to the pacific coast (canada and usa), bark is the part where the active alkaloid was found 

  • Use by indigenous north americans along west coast 

    • Used for stomach ache 

    • Used for cancerous tumors 

  • 50’s-90’s ethnobotanical knowledge was not considered in drug discovery 

    • Didn't think of natural products, set them back 

  • NCI - looking for new cancer drugs, teamed up with USDA due to lack of funding 

    • No consideration of indigenous knowledge or past history 

    • Saw potential for yew trees in anti-cancer drugs 

    • Discovered Bower manuscript - ayurvedic medicine 

      • Detailed use of trees in anti-cancerous tumor 

    • Started testing it on cancers, found it to be cytotoxic 

      • 12 kg of bark to get 0.5g of active alkaloid 

      • No longer sustainable due to the large amount of pacific yew required per year (trees almost went extinct in a couple years)

      • Active alkaloid - TAXOL, later renamed Paclitaxel 

        • 1971 discovered chemical structure, important for creation of synthetics 

          • Studied its mode of action and began clinical trials 

          • 1994 approved for breast and ovarian cancer, more recently prostate cancer 

    • Semisynthetics of paclitaxel 

      • Baccatin III, found in the leaves and small branches in a different species of the yew tree 

      • Large fast growing tree 

Mayapple or American Mandrake 

  • Native to North america 

  • Herbaceous, umbrella shaped leaves and grows from rhizomes which is used medicinally 

  • Use as laxative by north american indigenous peoples 

    • European colonies used as laxative and venereal warts, cancerous tumors, and polyps (mass of tissue with a root)

  • Phenolic - podophyllotoxins 

    • Cytolytic - kills cells 

    • Effects bone marrow, caused cancellation in research 

    • Potent antiviral agent, used to effect external genital warts 

  • Mechanisms - anti-mitotic, prevents formation or elongation of microtubules

  • Analogous - semi synthetics 

    • Teniposide, Etoposide 

      • E = for leukemia, brain and bladder tumors 

      • T = later, used for childhood leukemia 

    • Topoisomeraze enzyme  - inhibits the structure of DNA, uncoils it 

Tree of Joy 

  • Native to china and tibet 

  • Deciduous tree, used in traditional chinese medicine 

  • Bark, roots and fruit used 

  • Ethnobotanical information ignored slowing progress 

  • USDA looking for cortisone precursors 

    • Found alkaloid camptothecin - effects gastrointestinal tumors 

      • Topoisomerase affected 

      • Analogues 

        • Topotecan - ovarian cancer 

        • Irinotecan - colorectal cancer 

        • Lutotecan and extotecan - breast cancer 

      • Now researching antiviral activity and AIDS 

    • Stopped research due to severe effects, until 1985 when research started again 

  • Chinese research found better results and to be useful 

    • Quickly developed semi-synthetics 

Petty Surge

  • Small annual herb

  •  Native to europe and western asia 

  • Weedy in australia and north america 

  • Use in australia 

    • Spurge sap used on skin lesions and different types of skin cancers (basal cell carcinomas)

    • Saw it works and researchers started clinical trials (2012)

      • Effective against non-melanoma skin cancers 

        • Basal cell carcinomas 

        • Premalignant actinic keratosis 

          • Actinic keratosis - pre-cancer

  • Creation of gel - ingenol mebutate 

    • Kills cell and promotes normal cell growth 

    • Targets vasculature, stops the blood vessel proliferation 

    • Immune system boosting properties 

Dysoxylum

  • Mahogany family 

  • Perennial tree 

  • Found in india, southeast asia, and china 

  • History in ayurvedic medicine 

  • Fruit used for anti-inflammatory, diuretic (fluid release), central nervous system depressant 

    • Other species used for rheumatic 

  • Chroane alkaloid -  rohitukine

    • Bark 

    • Semi synthetic - flavopiridol 

      • Inhibits cyclin-dependent kinases, stops cell cycle progression and promotes apoptosis (cell death 

      • First drug effective against kinase inhibition in human clinical trials 

      • Used in rheumatoid arthritis, antiviral agent, contraceptive drug (kills cells)

      • Orphan status in the USA for leukemia 

        • Diseases that don't affect lots of people so don't need to worry about it, status means its used to treat these types of diseases 

Plum Yew 

  • Coniferous 

  • Indigenous to japan 

  • Used in china nad us 

  • Bark extracts used 

    • Leukemia and other types of tumor cells 

  • NCI and USDA 

    • Screamed and testes 

  • Alkaloids 

    • Homoharingtonine - or omacetaxine 

      • Leukemia 

    • Synthetics 

      • Imatinib - used in treatment of leukemia, replaced omacetaxine 

        • Inhibits enzymes specific to cancer cells 

        • Resistance quickly developed 

    • Prevents protein synthesis 

Maytenus

  • Woody tropical plant, mostly concerned with genus 

  • Shrub found in ethiopia, northeast africa 

  • Historical use 

    • South america - medicinal purposes 

    •  Africa - used to treat different cancer like treatment 

  • USDA-NCI look for plants to help with cancer treatment 

  • Maytenus buchanii

    • Vine speie 

    • Native to kenya 

    • Use wood and bark to get to the anti-cancer agents 

    • Over harvested 

  • Active alkaloid - maytansinoid

    • Come from actinomycete bacteria 

    • First time found in plants 

  • Maytansine - isolated from plant species 

    • Effects mitosi 

    • Binds to same sights a rosy periwinkle does not, more toxic 

    • Binds to tubulins and stops binding 

    • Start testing on phase I and II cancer trials 

      • Look for tolerable doses that are effective and how well people can handle 

      • Phase 2 is taking highest dose that works and people can handle and then start using it to see how it works 

    • People cannot tolerate it, severe reactions in the CNS (brain and spinal cord)

  • Targeted deliver 

    • Carrier molecule deliver cytotoxic agent to cancerous tumor 

    • Carrier molecules are antibodies that attack cancer

  • Semi Synthetics 

    • Developed to facilitate reliable target delivery 

    • More effective at attaching to monoclonal antibodies 

    • Mertansine - synthetic, linked to monoclonal antibodies 

    • Emtansine 

    • Trastuzumab emtansine - approved in 2013 

    • Lorvoluzumab mertansine - small cell lung cancer, orphan status