SBI242 - Week 11.docx

**SBI242 -- Week 11** Drugs affecting Neoplastic Diseases Treatment of cancer Neoplasia - uncontrolled proliferation and spread of abnormal cells of the body. This growth is uncoordinated and persists after the stimulus provoking the growth ends. Causes: Cell death Interfere with organ functio...

**SBI242 -- Week 11** Drugs affecting Neoplastic Diseases Treatment of cancer Neoplasia - uncontrolled proliferation and spread of abnormal cells of the body. This growth is uncoordinated and persists after the stimulus provoking the growth ends. Causes: Cell death Interfere with organ function Organ failure Characteristics of abnormal cells are inherited indefinitely by successive generations of cells. The biological capabilities acquired by human cells during development of cancer have been termed 'cancer hallmarks' listed below: 1. Sustaining proliferative signalling 2. Evading growth suppressors 3. Activating invasion and metastasis 4. Enabling replicative immortality 5. Inducing angiogenesis 6. Resisting cell death 7. Dysregulating cellurlar energetics -- emerging hallmarks 8. Avoiding immune destruction -- emerging hallmarks 9. Genome instability and mutation -- enabling characteristics 10. Tumour-promoting inflammation -enabling characteristics Antineoplastic drugs can be distinguished based on [four broad strategies]: 1. non-selectively blocking the cell cycle (cytotoxic drugs) 2. targeting hormone sensitive pathways (hormonal drugs) 3. targeting mutated pathway regulators (non-cytotoxic drugs) 4. enhancing the immune response to cancer (immunomodulatory drugs) Non-selectively blocking the cell cycle (cytotoxic drugs) Cytotoxic drugs act by inhibiting the synthesis of nucleic acids, DNA, RNA or proteins that are required in order for the cell cycle to proceed. Targets of cytotoxic drugs include: - Synthesis of proteins and nucleic acids -- inhibit the transcription of DNA to messenger RNA. E.g. Folic acid antagonists. - DNA replication and topoisomerases -- inhibit the 'supercoiling' of DNA fragments. E.g. Campothecins. - Chromosome duplication and telomerase -- an enzyme called telomerase prevents the shortening of the chromosome, keeping it viable. Therefore, telomerase inhibitors enhance shortening rendering the chromosome in cancer cells unviable. Targeting Hormone-sensitive pathways (Hormonal drugs) Growth of some tumours depends on stimulation of neoplastic cells by particular hormones. For example: - breast cancer is stimulated by oestrogens - prostate cancer by androgens - thyroid cancer by thyroid-stimulating hormone. These cancers may be effectively suppressed by drugs that suppress synthesis or secretion of the hormone, or by surgical removal or irradiation of the gland producing the hormone. E.g. tamoxifen (an anti-oestrogen). Targeting Mutated Pathways (non-cytotoxic drugs)\ These drugs can be small molecules or therapeutic proteins (e.g. monoclonal antibodies). They typically inhibit specific pathological (i.e. mutated) pathways that contribute to the dysregulation of the tumour cell cycle or tumour cell functions. They include: - tyrosine kinase inhibitors (e.g. imatinib) - cyclin-dependent kinase inhibitors (e.g. palbociclib) - serine threonine kinase inhibitors (e.g. everolimus) - histone deacetylase inhibitors (e.g. vorinostat) - replication checkpoint inhibitors (e.g. olaparib) - monoclonal antibodies that block interaction of growth factors or their receptors (e.g. bevacizumab). Mutated pathways that have been implicated in tumour development, proliferation or metastatic dissemination include; - *[Cyclins]* -- subunits of protein kinases that control mitosis and regulate transcription and regulation factors - *[growth factors]* - involved in signal transduction pathways and stimulates tumour proliferation - *[tyrosine kinases]* - a phosphorylating enzyme. Can promote proliferation. - *[serine-threonine kinase]*s - regulating cell growth and controls protein synthesis and angiogenesis - *[PI3 kinases]* - involved in cell growth, proliferation and differentiation - *[mitotic regulators]* -- regulate the inheritance of genetic traits - *[Checkpoints]* - checkpoints during mitosis ensure that any damaged DNA can be blocked and mutations during mitosis prevented. - *[tumour suppressor genes and proteins --]* prevent profliferation. E.g TGFβ-1. p53 proteins promote genes that activate apoptosis. Enhancing Immune Response to Cancer (Immunomodulatory Drugs) Mutated DNA often causes the production of abnormal proteins known as tumour antigens. Tumour antigens on the cell surface mark mutated cells as 'non-self', targeting them for destruction by immune cells; the immune system eliminates mutated cells on a daily basis. Cancer cells have the ability to avoid immune destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells, thus they can proliferate and form a tumour. Proposed mechanisms by which cancer cells avoid immune destruction include: 1. reducing expression of tumour antigens on their surface 2. expressing proteins on their surface that induce immune cell inactivation 3. inducing cells in the tumour microenvironment to release substances that suppress immune responses. Therapeutic immunomodulatory strategies include: - immune checkpoint modulators (e.g. pembrolizumab) - antineoplastic antibodies (e.g. trastuzumab) - immune system modulators (e.g. interferon alpha) - immune cell therapy (e.g. tumour-infiltrating lymphocytes) - cancer vaccines (e.g. Gardasil). Inflammation and Cancer Inflammatory cells and mediators such as cytokines, interleukins, interferons, reactive oxygen species, angiogenic growth factors, TNF-α and protease enzymes, many of which can enhance growth of cells, act as cancer promoters and promote angiogenesis. Cancers associated with inflammation include: human papilloma virus, hepatitis B virus and Epstein--Barr virus. *[Gastric carcinoma]* - peptic ulcers and infection by Helicobacter pylori. Chronic inflammatory conditions include; ulcerative colitis and Crohn\'s disease, and hepatitis C. Antineoplastic Drugs Cytotoxic Antineoplastic drugs -- act by interfering with cell proliferation or replication *[Common adverse effects include]*: myelosuppression (impaired bone marrow production of blood cells), alopecia, gastrointestinal tract (GIT) irritation, infertility, possible secondary malignancies and tissue damage after inadvertent extravasation (injection solution leaking into tissues) and febrile neutropenia resulting from myelosuppression (dose related). Alkylating Agents First class of modern era antineoplastic drugs *[Mechanism of Action]* Highly reactive alkyl (E.g., methyl, ethyl) groups that bind to nitrogen atoms in guanine bases of DNA, forming strong bonds. These bonds between guanine bases cause breakage of the DNA strand when the cell initiates repair or replication, which leads to apoptosis (programmed cell death). The main drugs classes of alkylating agents are; the nitrogen mustard analogues, nitrosoureas and platinum-based agents. Antimetabolites Antimetabolites impair the utilisation of endogenous chemicals involved in metabolic processes. These drugs are typically similar in structure to the endogenous chemical. *[Mechanism of Action]* They inhibit enzymes involved in pathways for nucleic acid synthesis and/or act as false 'building blocks', causing damaged polymers of nucleic acids to be built up into impaired DNA and RNA in the cancerous cell. - *[Folic acid antagonists]* - Folic acid is an essential co-factor for the synthesis of purines nucleotides and thymidylate; thus they interfere with thymidylate synthesis in the cancer cell. E.g., Methotrexate. - *[Purine and pyrimidine antagonists]* - incorporated into DNA strands in place of the true bases leading to improper base pairing and improper transcription to RNA. E.g., Mercaptopurine and Fluorouracil. Cytotoxic Antibiotics Cytotoxic antibiotics are defined as antibiotics because they are isolated from a microorganism (usually fungi) and act against another organism (neoplastic cells). *[Mechanism of Action]* - directly binds to DNA (intercalating), thus inhibiting DNA and RNA synthesis - stabilises the DNA-topoisomerase II complex, preventing relaxation of supercoiled DNA - produces reactive free radicals that damage tumour cells. Anthracyclines are complex polycyclic molecules derived from Streptomyces bacteria. In addition to standard adverse effects, cardiac toxicity may occur with all drugs in this class. Other drugs include; dactinomycin, bleomycin and mitomycin. Mitotic Inhibitors Isolated from plants *[Mechanism of Action]* - During the metaphase stage of mitotic division replicated chromosomes line up on a spindle formed by microtubules. - Mitotic inhibitors bind to tubulin, a constituent of microtubules, which inhibits its polymerisation into microtubules and disrupts spindle formation, thus stopping cell mitosis. Examples of mitotic inhibitors include - Taxanes and vinca alkaloids *[Adverse effects]* - Neurotoxicity is a common and major dose-limiting toxicity for vinca alkaloids. often presents as autonomic (e.g., orthostatic hypotension, paralytic ileus and urinary retention) or peripheral neuropathy (e.g., paraesthesia, paralysis). Epothilones Natural epothilones are extracted from the myxobacterium Sorangium cellulosum. *[Mechanism of Action]* similar to those of taxanes, but early trials suggest that epothilones may have better efficacy and milder adverse effects. Topoisomerase inhibitors *[Camptothecins]* (topoisomerase I inhibitors) - inhibit topoisomerase I enzymes, which are involved in untwisting, nicking and resealing of DNA strands during DNA duplication, which causes breaks in double-stranded DNA, blocking macromolecular synthesis leading to tumour cell death. *[Podophyllotoxins]* (topoisomerase II inhibitors) - resulting in DNA strand breaks and inhibition of cell division in the late S and G2 phases of the cell cycle. *[Indicated]* - in the treatment of leukaemias and lymphomas Proteasome inhibitors Proteasomes are large protease-containing complexes in cells in which regulatory proteins are degraded. *[Mechanism of Action]* -- inhibition of proteasome function kills cells. E.g. Bortezomib indicated for the treatment of lymphoma and multiple myeloma. Topical cytotoxic agents Topical formulations of antineoplastic agents have been developed for application to skin lesions; these may be equally effective (compared to cryotherapy or surgery) for removal of SCCs and BCCs, with less facial scarring. - Examples include - Fluorouracil cream 5% (pyrimidine antimetabolite), and Methyl aminolevulinate hydrochloride (photosensitising -- produces ROS). Hormonal Antineoplastic drugs Drugs used in treatment of neoplasia that is sensitive to hormonal growth. E.g., growth of prostate cancer is stimulated by androgens, breast cancers by oestrogens, and thyroid cancer by thyrotrophin. Less toxic than cytotoxic antineoplastics Include corticosteroids, androgens and anti-androgens, oestrogens and anti- oestrogens, progestogens, hormone synthesis inhibitors and analogues of gonadotrophin-releasing hormone (GnRH) Androgens and Anti-androgens Androgens such as testosterone are used to treat advanced breast cancer if surgery, radiation and other therapies are inappropriate or ineffective. Anti-androgens inhibit uptake or binding of androgens at their target cells or receptors. These drugs suppress ovarian and testicular steroidogenesis, thus inducing a 'medical castration', and are indicated in combination with surgery and a GnRH analogue in advanced prostate cancer. Oestrogens and Anti-oestrogens Oestrogens used to treat advanced breast carcinoma in postmenopausal women. E.g. diethylstilboestrol (DES) and ethinylestradiol (EE) Anti-oestrogens are drugs of first choice in postmenopausal breast cancers that are oestrogen receptor (ER)-positive. E.g. Raloxifene Selective ER modulators (SERMs) were designed to block ERs in breast cancers but maintain ER agonist actions in tissues such as bone and the cardiovascular system where oestrogen has protective actions. E.g. tamoxifen and toremifene. Drugs that induce CYP2D6 or CYP3A4 increase the metabolic activation of tamoxifen and may enhance the therapeutic and toxic effects. Tamoxifen increases the anticoagulant effects of warfarin. Aromatase Inhibitors Mechanism of Action In the biochemical synthesis of oestrogens, a critical stage is 'aromatisation' of the steroid A ring, from testosterone to oestradiol. Thus, these drugs inhibit the synthesis of oestrogens by inhibiting the aromatision of the steroid A ring. E.g.anastrozole,exemestaneandletrozole. Indicated for use in women with natural or induced postmenopausal status, whose breast cancer has progressed despite anti-oestrogen therapy. Aromatase inhibitors do not block synthesis of glucocorticoids or mineralocorticoids. Gonadotrophin- releasing Hormone Analogues and Antagonists *[Mechanism of Action]* - Suppress production of gonadotrophins from the pituitary gland, and thus have indirect anti-androgenic and anti-oestrogenic effects. E.g. goserelin, leuprorelin and triptorelin. - Indicated for gonadal suppression in endometriosis, polycystic ovary syndrome, prostatic and premenopausal breast cancer, and prostate cancer where they cause chemical castration. - GnRH antagonist degarelix - blocks pituitary receptors, thus reducing testosterone levels and causing regression of prostate cancer and lowered prostate-specific antigen. Somatostatin Analogues of somatostatin are used to treat cancers of the pituitary gland that produce excess growth hormone (causing acromegaly) and in carcinoid tumours of the GIT that secrete excess 5-hydroxytryptamine. E.g. octreotide and lanreotide. Somatostatin analgogues are associated with common GIT adverse reactions. Corticosteroids *[Mechanism of Action]*- Glucocorticoids retard lymphocytic proliferation by suppressing white cell production. E.g. Prednisone and dexamethasone. They are indicated in the management of lymphocytic leukaemias and lymphomas. Also used as adjuncts with radiation therapy to decrease oedema in critical areas such as the brain and spinal cord, and as anti-inflammatories. Non-Cytotoxic Antineoplastic Drugs Also commonly referred to as 'targeted therapies' The two main classes of non-cytotoxic antineoplastic drugs are; - the small molecule kinase inhibitors (KIs) -- names end in 'nib' - antineoplastic monoclonal antibodies (mAbs) -- names end in 'mab' These drugs mainly act on families of membrane-bound kinase-linked receptors, in particular: - platelet-derived growth factor receptor (PDGFR) - human epidermal growth factor receptor (HER) - epidermal growth factor receptor (EGFR) - vascular endothelial growth factor receptor (VEGFR). They specifically block signal transduction pathways causing impaired tumour growth and metastatic dissemination - typically better tolerated than cytotoxic drugs. PARP inhibitors BRCA1 and 2 are proteins that repair double-strand DNA breaks. Mutations in the BRCA 1 or 2 lead to errors in DNA repair that can eventually cause breast or ovarian cancer. Poly (ADP-ribose) polymerase (PARP) 1 is an enzyme that repairs single-strand breaks or 'nicks' in DNA. Mechanism of Action PARP inhibitors prevent PARP 1 from repairing single-strand breaks in tumour DNA resulting in multiple double strand breaks to form in tumours with BRCA1 or 2mutations. These breaks cannot be repaired, and lead to cell death. E.g., Olaparib (Lynparza), Niraparib (Zejula), Rucaparib (Rubraca), and Talazoparib (Talzenna). mTOR inhibitors The mammalian target of rapamycin (mTOR) is a central serine/threonine kinase that regulates metabolism and physiology. E.g. Everolimus and temsirolimus. Mechanism of Action - indirectly inhibit the mTOR pathway by binding to the intracellular protein FKBP-12. - the protein--drug complex blocks the activity of mTOR kinase, inhibiting angiogenesis and tumour cell proliferation, growth and survival. *[Everolimus]* is indicated in the treatment of renal cell cancer, pancreatic neuroendocrine tumour and breast cancer. *[Temsirolimus]* is indicated in the treatment of renal cell cancer and mantle cell lymphoma. *[Adverse effects]* - electrolyte disturbance (hypokalaemia and hypophosphataemia) and metabolic disturbance (hyperglycaemia, hypercholesterolaemia and hypertriglyceridaemia); also, anaemia, hepatotoxicity, lymphopenia, nephrotoxicity, neutropenia, pneumonitis and thrombocytopenia. Histone De-acetylase inhibitors Used for many years in the treatment of psychological and neurological disorders. Recent interest in their role as cancer treatments or adjuncts. Mechanism of Action Induce expression of cyclin-dependent kinase inhibitor 1 (p21), a regulator of the tumour suppressor p53 -- Thus increasing tumour suppression activity. E.g. romidepsin and vorinostat. They are indicated for the treatment of peripheral T-cell lymphoma and multiple myeloma. Immunomodulatory drugs physical barriers prevent pathogens from entering the body. If a pathogen breaches these barriers, the innate immune system mounts an immediate, but non-specific response. If a pathogen evades this non-specific response, the adaptive immune system mounts a response tailored to the specific pathogen or pathogen-infected cells. The function of the immune system in cancer patients is important because: - cancer and cancer treatments can weaken the immune system, predisposing patients to potentially life-threatening infections, and - the immune system itself may be harnessed to help fight certain types of cancer Immune checkpoint inhibitors Many cancers protect themselves from the immune system by using/activating immune checkpoints to inhibit T-cell signalling. - There are two classes of immuno-modulatory drugs that inhibit cancer cells from utilizing these immune checkpoints: CTLA4 inhibitors and PD-1/PD-L1 inhibitors. 1.***[CTLA4 inhibitors]*** - T lymphocyte associated antigen 4 (CTLA4) is an inhibitory checkpoint that blocks the cytotoxic reaction mounted by T-cells against a tumour. By blocking this inhibitory checkpoint, CTLA4 inhibitors result in the activation of the protective T-cells to destroy cancer cells. E.g. Ipilimumab. Indicated for the treatment of metastatic melanoma; it is also being trialed against lung, head and neck, bowel, prostate and kidney cancers. *[Adverse effects]* - enterocolitis, hepatitis, dermatitis and neuropathies. 2\. ***[PD-1/PD-L1 inhibitors]*** - Programmed cell death receptor 1 (PD-1) is a cell surface receptor that plays an important role in mediating the immune system by suppressing or co-stimulating T-cell activity. Ligand binding at the cell surface by programmed death ligand 1 (PD-L1) or 2 (PD-L2) at PD-1 receptors suppresses T-cell activation. Several cancers overexpress the ligand for PD-1 (PDL-1) as a mechanism for avoiding immune destruction. PD-1 inhibitors block the interaction of PDL-1 with PD-1 and enhance T-cell-mediated destruction of cancer cells. E.g. Nivolumab and pembrolizumab - They are an important emerging therapies for several forms of cancer. - Indicated for the treatment of metastatic melanoma, non- small cell lung cancer and renal cell carcinoma. Interferons naturally occurring small protein molecules with antiproliferative and immuno-stimulating actions. Defects in interferon responses occur in many cancer- initiating cells. Two synthetic interferons are used in the treatment of cancer: - interferon alpha for its cytotoxic properties - interferon gamma for its immunostimulatory properties *[Interferon alpha]* - used in the treatment of malignant melanoma, mycosis fungoides, myeloproliferative disorders, and renal cell cancer. *[Interferon gamma]* - used as an adjunct to reduce serious infections in chronic granulomatous disease. *[Adverse effects:]* flu-like syndrome with fever, chills, muscle pain, loss of appetite and lethargy. High dose - cardiotoxicity, myelosuppression, nausea and vomiting, and neurotoxicity. **Levamisole** Levamisole was initially used clinically as a treatment for intestinal worm infestations. It was found to have useful immunostimulant effects, enhancing T-cell-mediated immunity and macrophage actions. Levamisole is used in combination with 5-fluorouracil to treat colorectal carcinoma. **Aldesleukin** A recombinant version of human interleukin-2 (IL-2) Stimulates T-cell proliferation, is a co-factor in enhancing growth of natural and lymphokine-activated killer cells and increases production of interferons. *[Indications]* - metastatic renal cell carcinoma, melanoma and thymoma, and after bone marrow transplant. *[Adverse effects]* - oedema, anaemia, thrombocytopenia and hypotension **Granulocyte colony-stimulating factors (G-CSFs)** Stimulate neutrophil precursor cells to produce phagocytes, reducing duration of neutropenia and risk of infections. Administered after myelosuppressant cytotoxic chemotherapy or bone marrow transplant to reduce immuno-suppression adverse effects. E.g. Filgrastim, lenograstim and pegfilgrastim. **Non-vaccine bacillus Calmette-Geurin therapy** BCG is live, attenuated Mycobacterium bovis that produce a local inflammatory reaction resulting in elimination or reduction of superficial bladder tumour lesions. - Used in the treatment of early-stage bladder cancer. Immunocompromised patients are at risk of systemic tuberculosis infection; *[Other adverse effects]* - urinary tract pain and dysfunction, fever and malaise.