Cancer Chemotherapy 3: Drug Classes PDF

latrobe.edu.au Cancer chemotherapy 3: Classes of drugs Dr Ross O’Shea [email protected] La Trobe University CRICOS Provider Code Number 00115M  History of cancer chemotherapy 1940s: nitrogen mustards (chemical warfare agents) - Goodman &...

latrobe.edu.au Cancer chemotherapy 3: Classes of drugs Dr Ross O’Shea [email protected] La Trobe University CRICOS Provider Code Number 00115M  History of cancer chemotherapy 1940s: nitrogen mustards (chemical warfare agents) - Goodman & Gilman 1948: folic acid antagonists (antimetabolites) 1950s: 6-MP, vinca alkaloids 1965: combination therapy Types of cancer chemotherapies Radiopharmaceuticals (“nuclear medicine”, “radiation oncology”) Anti-neoplastic agents Cytotoxic agents 1 Alkylating agents 2 Antimetabolites 3 Antitumour antibiotic agents 4 Mitotic inhibitors 5 Hormone chemotherapy / Miscellaneous  Cytotoxic agents … May have different sites of action on cell division cycle ALL inhibit cell replication ⇒ (anti-proliferative) Are classified as cell cycle specific OR cell cycle non-specific Classification is important for drug choice  (1) Alkylating agents Contain alkyl groups (methyl –CH3, ethyl –CH2CH3) React with the DNA to form strong bonds Hold DNA strands together (like a zipper that’s stuck) Drugs prevent DNA from unravelling for DNA replication / RNA transcription Cell cycle slowed / stopped – mainly at S phase  Synthesis Used with permission: http://en.wikipedia.org/wiki/File:Cell_Cycle_2.svg  (1) Alkylating agents Segment of DNA  (1) Alkylating agents Examples: Nitrogen mustards: – Chlorambucil – Cyclophosphamide (pro-drug) Nitrosoureas: Highly lipophilic – Carmustine – Lomustine Others (these are just examples!)  (2) Antimetabolites Analogues of folic acid OR purine / pyrimidine bases Inhibit enzymes involved in pathways of macromolecular synthesis OR are false “building blocks”, causing impaired polymers of nucleic acids to be assembled 3 main groups: – Folate antagonists e.g. methotrexate (pro-drug) (Used since 1940’s, less toxic than previous treatments) – Purine antagonists e.g. mercaptopurine – Pyrimidine antagonists e.g. fluorouracil  (2) Antimetabolites: folate antagonists Folate (vitamin B9) – important factor in many biological reactions, e.g. essential for production of DNA and RNA Initial observation: children with leukemia had worse outcomes when taking folic acid Folate antagonists mainly act by inhibition of the enzyme dihydrofolate reductase  (2) Antimetabolites: folate antagonists CH3 H NH2 OH Methotrexate Folic Acid has 1,000x greater affinity for the enzyme than folate does Dihydrofolic acid (DHFA) Dihydrofolate Folate antagonists reductase Inhibit action of dihydrofolate Tetrahydrofolic acid reductase (THFA) Synthesis of purines and pyrimidines (incorporated into DNA and RNA)  (2) Antimetabolites: purine & pyrimidine antagonists Can be incorporated into DNA strands in place of proper base Form permanently modified DNA Causes improper base pairing -> improper transcription to RNA May also act as inhibitors on enzymes of DNA synthesis Phase specific – act particularly at the S phase of cell cycle  (2) Antimetabolites: purine & pyrimidine antagonists  (3) Antibiotic anti-tumour drugs 2 main groups: – Anthracyclines – Bleomycins Called antibiotics because compounds isolated from one type of organism (fungi) and act against anther type of organism (neoplastic cell)  (3) Antibiotic anti-tumour drugs: anthracyclines 1950’s – attempts to isolate anti-cancer compounds from microbes in soil e.g. daunorubicin, doxorubicin, idarubicin May be multiple MOA, not fully understood Bind directly to DNA ∴ inhibit DNA and RNA synthesis Inhibit topoisomerase II Intercalate with DNA to impair DNA transcription Cell-cycle specific – S phase Cardiac toxicity, lifetime maximum dose (these are just examples!)  (3) Antibiotic anti-tumour drugs: bleomycins e.g. bleomycin, mitomycin (from Streptomyces species) Block incorporation of thymidine into DNA, also degrade DNA that is already formed Cell-cycle non-specific – G2, M, G0 (these are just examples!) (3) Antibiotic anti-tumour drugs: bleomycins  (4) Mitotic inhibitors Natural products – from plants 3 groups: – vinca alkaloids – podophyllotoxins – taxanes Main action at the metaphase stage of mitotic division  (4) Mitotic inhibitors These agents bind to tubulin Tubulin constituent of microtubules ∴ disruption of spindle formation and “freezing” of mitosis in metaphase Cell-cycle specific - M phase (4) Effect of mitotic inhibitors Normal mitosis Effect of mitotic inhibitors  (4) Mitotic inhibitors: vinca alkaloids From Vinca (Europe, Africa, Asia) “periwkinke” e.g. vincristine vinorelbine (oral) vinflunine vinblastine Relatively non-toxic compared to other cytotoxic agents Exceptionally neurotoxic – Special precautions to not give intrathecally (these are just examples!)  Intrathecal vinca alkaloids https://www.bmj.com/rapid-response/2011/11/02/criminal-negligence- another-unfortunate-incidence-intrathecal-vincristine- Another 17 cases in US since then, now 150 worldwide since 1985 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959612/  (4) Mitotic inhibitors: podophyllins Originally isolated from rhizomes of May Apple e.g. etoposide teniposide As well as effects in M phase, also kill cells in the S and G2 phase Used in leukaemias and lymphomas (these are just examples!)  (4) Mitotic inhibitors: taxanes From Taxus (yews) e.g. paclitaxel docetaxel Also stimulate the immune response Used to treat breast, lung and ovarian cancer (these are just examples!)  (5) Hormonal treatment Treatment of neoplasia that are sensitive to hormonal growth controls e.g. for thyroid, breast and prostate cancers Includes: corticosteroids androgens/anti-androgens oestrogens/anti-oestrogens progestogens analogues of gonadotrophin releasing hormone (GnRH) (these are just examples!)  (5) Miscellaneous Treatments Antineoplastic antibodies – Bind to a specific antigen or factor which is needed by a cancer cell to proliferate VEGF (Vascular Endothelial Growth Factor) – Needed to create new blood vessels for tumours – Blocked by bevacizumab (Avastin) EGFR (Epidermal growth factor receptor) – Needed for new ‘endothelial cells’ – SCC, head and neck, colorectal – Cetuximab (Erbitux) (these are just FYI!)  (5) Miscellaneous Treatments HER2 (human epidermal growth factor receptor 2) – Overexpression in some tumours, such as breast and gastric – Blocked by Trastuzumab (Herceptin) All antineoplastic antibodies share the same set of side effects (plus some unique others) – Immune reactions – Increasing individual drug resistance – COST! (these are just FYI!)  (5) Miscellaneous Treatments Thalidomide (and derivatives) – Used for blood cancers (leukaemia, lymphoma and multiple myeloma) – Unknown mechanism of action Probably immunosuppressive and anti- angiogenesis – BIRTH DEFECTS! Pregnancy Category X (these are just FYI!)  From this video you should be able to: Describe the classes of available cancer chemotherapies and their modes of action (not individual drugs) Explain some of the problems associated with cancer chemotherapy