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ANTICANCER DRUGS PowerPoint Presentation

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Description : Check out this medical presentation on Pharmacology, which is titled "Anticancer Drugs", to know about the Anticancer Drugs.

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Assoc. Prof. Ivan Lambev www.medpharm-sofia.eu ANTICANCER DRUGS
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Possible causes of cancer Physical agents (radiation, mobile phones ?) Chemicals (carcinogens, including smoking) Hereditary factors Effectiveness of the immune system (virus infections: Ca collum uteri) Stress, > BMI (GI cancer), some drugs (cyclophosphamide, estrogens, tamoxifen)
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Uncontrolled proliferation Can be invasive Can metastasize Lack of function (lack of differentiation) Characteristics of cancer cells
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Normal cells Growth is controlled by growth factors and growth inhibitory factors Cancer cells Inactivation of tumor-suppressor genes Activation of proto-oncogenes
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ANTICANCER TREATMENT  surgery  radiotherapy (irradiation)  chemotherapy  supportive therapies NB! NB!
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The sensitivity of a cancer to treatment depends on the growth fraction – that is the fraction of cells undergoing mitosis at any time.
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The fraction of cell division in Burkitt’s lymphoma is 100% and this tumor is very sensitive. In contrast the growth fraction represents less than 5% of cells in a carcinoma of the colon and this explains its resistance to chemotherapy.
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However, metastases from colonic carcinoma, deposited in the liver and elsewhere initially, have a high growth fraction and are sensitive to chemotherapy, which is frequently given following surgical removal of primary tumor.
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Different forms of cancer differ in their sensitivity to chemothe- rapy. The most responsive are rapidly proliferating tumors: lymphomas leukemias choriocarcinoma testicular carcinoma
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Solid tumors show a poor response: colorectal carcinomas adrenocortical carcinomas squamous cell bronchial carcinomas
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An intermediate response is shown by other cancers: bladder head and neck oаt cell bronchogenic carcinoma sex-related cancers of the breast, ovary, endometrium, prostate
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Solid tumors – surgery or irradiation, plus CHEMOTHERAPY “Non-solid tumors” – CHEMOTHERAPY Metastases – CHEMOTHERAPY
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Myelotoxicity (reduction of leukocytes increases susceptibility to infections) Hair loss Adverse effects Most of the anticancer agents have a limited selectivity and damage all dividing cells. As a result general adverse effects are:
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Damage to GI tract Impaired wound healing Depression of growth Nausea and vomiting Carcinogenicity (in rare cases) Reproductive toxicity (PRC: D/X) Kidney damage Hepatotoxicity
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Resistance to cytotoxic drugs (primary or acquired) in 90% of cases – mechanisms: Increased rate of synthesis of target enzyme (dihydrofolate reductase and methotrexate) Increased repair of DNA (alkylating agents) Insufficient activation of prodrug – cytarabine (does not undergo phosphorylation) Multi Drug Resistance – increasing action of membrane efflux system (P-gp 170 and 190), etc.
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Strategy to avoid resistance Use 3 or 4 anticancer drugs together or in sequence, e.g. treatment of lymphomas: COP treatment (COP – acronym) – Cyclophosphamide – Oncovin® (vincristine) – Prednisolone
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Each drug should be an active anticancer drug in its own right. Each drug should have a different mechanism of action and target site within the cancer cell (this will increase efficacy and will reduce the resistance). Each drug should have a different site for any organ-specific toxicity. Criteria for selecting combinations
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The dosage of many antineoplastic drugs is carried out according to the body surface of the patient, calculated in square meters (m2) by means of nomogram according body mass in kg and height in cm. The best treatment regimens are become the "gold standard" for treatment of cancer. They are develop and annually update by world oncotherapeutic teams.
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Prof. A. Dudov, MD, PhD President of Bulgarian Cancer Scientific Society
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Anticancer (antineoplastic) drugs I. Cytotoxic drugs (cytostatics) - Alkylators - Antimetabolites - Plant-derived drugs and their analogs - Cytotoxic antibiotics - Platinum coordination complexes II. Endocrine agents - Glucocorticoids - Sex hormones and antihormones
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III. Target drugs - Monoclonal antibodies (MAB) - Protein (tyrosine kinase) inhibitors - Inhibitors of production of TNF-α IV. Inhibitors of bone resorption and metastases V. Immunomodulators - Cytokines (ILs, IFNs) - Vaccines VI. Radiotherapy VII. Cancer supportive therapies
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CYTOTOXIC AGENTS The majority of cytotoxic agents inhibit the process of DNA synthesis within the cancer cells. Resting cells (those in the Go phase) are resistant to many anticancer drugs.
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Precursors Precursors Purine Pyrimidine Ribonucleotides Deoxiribonucleotides DNA RNA Proteins Methotrexate Mercaptopurine Alkylators Cis-platin Antibiotics Nitrosoureas Mitotic inhibitors Asparagine Asparaginase
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Action of cytotoxic agents on the cell cycle Cycle non-specific Alkylators Antibiotics Phase specific Antimetabolites Mitotic inhibitors
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 Alkylating agents These drugs were developed from the sulfur mustard gases used in the 1st WW trenches and which caused bone marrow suppression in addition to respiratory toxicity. Replacement of the sulfur atom by nitrogen allowed the first alkylating agents to be obtained.
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The important functional group is the di-(2-chlor-ethyl)-amine side chain: R—N CH2CH2Cl CH2CH2Cl The dichlorethylamine chains are highly reactive and produce alkylating groups which bind covalently to sites within the DNA such as N7 of guanine.
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Chlorambucil Cyclophosphamide a) First alky- lators are di-(2-chlor ethyl)- amines: Nitrogen mustards
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Cyclophosphamide and Chlorambucil are commonly used for Hodgkin’s and non-Hodgkin’s lymphoma, chronic lymphocytic leukemia. Cyclophosphamide is also used for immunosuppression in non-malignant disorders (severe rheumatoid disorders, myasthenia gravis, multiple sclerosis).
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Cyclophosphamide is a prodrug. One of its metabolites is acrolein. Acrolein causes bladder toxicity with haemorrhagic cystitis which can be prevented by prior treatment with Mesna. Bladder cancer may develop years after cyclophosphamide chemotherapy. Cancer
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b) Nitrosoureas (the other alky- lators) inhibit the synthesis of DNA, RNA, and proteins. Carmustine crosses BBB. It is used for brain tumors. Carmustine and Lomustine are used for the treatment of Hodgkin’s lymphoma.
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A number of useful chemothera- peutic agents have been produced by simple modifications to the structures of normal purine and pyrimidine bases.  Antimetabolites – produce lethal synthesis
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5-Fluorouracil (5-FU®: i.v.) – used for the treatment of carcinoma of stomach, colon, rectum, breast, and pancreas. Xeloda® (p.o.) – used in colorectal carcinoma. It is a prodrug of 5-FU with very high selectivity. Cytarabine: used in acute myeloid leukemias (It acts after phosphorylation) a) Analogues of pyrimidine 5-FU
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5-FU blocks thymidilate synthase
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b) Analogues of purine Mercaptopurine (6-MP) and Thioguanine (6-TG): used in childhood acute leukemia; Fludarabine Gemcitabine is an analogue of pyrimidine too. It inhibits DNA polymerase and impairs DNA synthesis. It is used in various carcinomas: non-small cell lung cancer, pancreatic cancer, bladder cancers, breast cancer.
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c) Folic acid antagonists Methotrexate, Pemetrexed, Ralitrexed Folic acid in its reduced form (THF – tetrahydrofolic acid) is essential for syn- thesis of the purine ring system. During these reactions THF is oxidized to dihydro- folic acid which has to be reduced by dihydrofolate reductase. Methotrexate inhibits dihydrofolate reductase and blocks purine and thymidine synthesis.
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Folic acid Methotrexate (It has immunosuppressive activity too.)
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Methotrexate is given for the treatment of: acute lymphoblastic leukemia non-Hodgkin’s lymphomas chorionepithelioma non-malignant disorders (such as psoriasis).
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Adverse effects of methotrexate Vasculitis Arachnoiditis Pharyngitis, pneumonitis Cystitis Vomiting Hepatotoxicity Renal dysfunction PRC: D
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 Plant-derived drugs and their analogs Vinca alkaloids Derivatives of Podophyllotoxin Taxans etc. They have cycle and phase specific action on the cell division.
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Vinca alkaloids are complex natural chemicals isolated from the periwinkle plant (Vinca rosea). Vinblastine Vincristine Vinorelbine (Navelbine®) They bind to tubulin and produce metaphase arrest. They are used in acute leukemia.
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(mitotic inhibitors)
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Podophyllum peltatum (May apple) Podophyllotoxin Epipodophyllotoxin Etoposide Teniposide Derivatives of Podophyllotoxin (epipodophyllotoxins)
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Etoposide Inhibits mitosis Acts in late S- or early G2-phases Used in treatment of lymphoma; lung, testicular, bladder and prostate cancer
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Taxans Docetaxel – in breast cancer Paclitaxel Inhibit the depolymerization of tubulin and block mitosis. (Taxus brevifolia)
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 Cytotoxic antibiotics (inhibit DNA replication)
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Daunorubicin Idarubicin Doxorubicin Epirubicin
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Mitomycin C – in cancer of the bladder (locally after TUR) Other antibiotics Bleomycin in: – testicular cancer – melanomas, sarcomas – squamous cell carcinomas
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Cis-platin binds to DNA and proteins. It has made a significant impact on the treatment of testicular teratoma and ovarian tumors. It has a long t1/2 (72 h) due to extensive protein binding and slow renal elimination. Renal toxicity is a major problem. Severe nausea and vomiting are often troublesome too. PRC: D.  Platinum coordination complexes
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II. Endocrine agents Some cancer arise from cell lines with steroid receptors. Steroid hormones cause remissions in certain types of cancer. They usually do not eradicate the disease, but can alleviate symptoms for a long period and do not depress the bone marrow.
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Glucocorticoids suppress lymphocyte mitosis and are used in combination with cytotoxic agents in treating of lymphomas, myeloma and to induce a remission in acute lymphoblastic leukemia.
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Hydrocortisone, Prednisone Dexamethasone, Prednisolone Glucocorticoids are also helpful in reducing oedema around a tumor. They have antiemetic activity too.
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 Estrogens suppress prostate cancer both locally and metastases, and provide symptomatic improvement. Gynecomastia is a common side effect. Ethinylestradiol Polyestradiol phosphate
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 Progestagens suppress endometrial cancer cells and lung secondaries: Gestonorone Medroxyprogesterone
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Androgens are used rarely in the treatment of carcinoma ovarii and uteri Testosterone Side anabolic effect:
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 Androgen antagonists suppress prostate cancer cells. Unwanted effects include: gynecomastia, decreased spermatogenesis, decreased libido. Bicalutamide, Cyproterone, Flutamide 1 2 3 PSA >> 5
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Cyproterone (Androcur®) p.o. i.m. – anti-aphrodisiac too.
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 Inhibitors of alpha-reductase Alpha-reductase converts testosterone in more active dihydrotestosterone. Finasteride is useful orally in the treatment of benign prostatatic hyperplasia.
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 Estrogen antagonists Fluvestrant, Toremifen Tamoxifen (p.o.) suppresses breast cancer cells. The trans isomer of Tamoxifen blocks competitively estrogen receptors. Adverse effects include hot flushes and amenorrhoea in premenopausal women and vaginal bleeding in postmenopausal women.
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 Aromatase inhibitors Aminoglutethimide Exemestane (Aromasin®) Formestane, Letrozole They inhibit aromatase and block conversion of androgens to estrogens. - Inhibition of aromatase reduces estrogen production in adipose tissue, skin, muscle, and liver of postmenopausal women (because ovarian aromatase is resistant to such inhibition!).
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Aromatase is also presented in the cells of two-thirds of breast carcinomas and about 80% of these tumors are estrogen- dependent. Aromatase inhibitors are used in postmenopausal women with advanced breast carcinoma. Side effects include symptoms of estrogen withdrawal, e.g. headache, hot flushes, and lethargy; dyspepsia, nausea, alopecia, skin rash, hypotension, tachycardia.
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Breast cancer
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Treatment with the aromatase inhibitor letrozole reduces the occurrence of distant metastases in Ca mammae
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 Gonadotrophin releasing hormone agonists (GnRHAs) Continuous daily administration of GnRHAs results in suppression of testicular and ovarian steroido- genesis due to decreased levels of LH and FSH with subsequent decrease in testosterone (in man) or estrogens (in women).
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Gonadotrophin releasing hormone agonists: Leuprolide (Leuproreline) Goserelin (Zoladex®) – 3.6 mg/30 days s.c. in: – palliative treatment of advanced prostatic carcinoma – endometriosis
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III. Target drugs They block receptors of the growth and other angiogenic factors: VEGF – vascular endothelial growth factor EGF – epidermal growth factor PDGF – platelet-derived growth factor PlGF – placental transfer growth factor TNF-α – tumor-necrosis factor alfa, etc.
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a) Monoclonal AntiBody (MAB) BEVACIZUMAB (Avastin®) – anti-VEGF agent blocks angiogenesis and the growth of new blood vessels. It is used to treat various cancers, including colorectal, lung, and kidney cancer, etc. Avastin®
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Colorectal cancer
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TRASTUZUMAB (Herceptin®) is part of a treatment plan for the adjuvant treatment of patients with HER2 overexpressing, node-positive HER2+ breast cancer. CETUXIMAB (an inhibitor of EGF receptor): used in metastatic colorectal cancer. www.breastcancer.org/symptoms
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b) Protein kinase inhibitors Imatinib (Glivec®): used for the oral treatment of chronic myelogenous leukemia Everolimus (Afinitor®) – mTOR inhibitor: mammalian Target Of Rapamycin) is used: in renal cancer, pancreatic neuroendocrine tumors, as an immunosuppressant to prevent rejection of organ transpalntants (including in drug-eluting coronary stents to prevent restenosis). Lapatinib, Pasopanib Sorefenib (used in renal and liver cancer)
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c) Inhibitors of the production of TNF-α: Thalidomide and analogs - in with Kaposi's sarcoma, glioblastoma, multiple myeloma, erythema nodosum leprosum)
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IV. Inhibitors of bone resorption and metastases
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The immune system probably contributes to the final removal of residual malignant cells, and most cytotoxic anticancer agents compromise immune responsiveness. V. IMMUNOMODIFICATORS
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 Cytokines – peptide regulators of inflam- matory and immune reactions. Interleukins, interferons, colony-stimulating factors, tumour necrosis factors.
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IL-2 produced by T-lymphocytes which activate cytotoxic killer cells. It is received by recombinant DNA technology. IL-2 has been given by i.v. infusion in patients with metastatic renal carcinoma. IL-2 causes many ADRs.
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Interferon alfa-2b (Intron® A) – in: chronic hepatitis, hairy cell leukemia AIDS-related Kaposi’s sarcoma renal carcinoma Interferons (alpha, beta, gamma) are glycoproteins produced as part of the natural host defenses to virus infections. They have antiviral activity, immunoregulatory function, reduce multiplication of cancer cells.
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Papular cutaneous Kaposi’s sarcoma Kaposi's sarcoma (KS) is a tumor caused by Human herpesvirus 8.
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 Vaccines BCG Immunotherapeuticum – locally in bladder cancer after TUR Silgard® and Cervarix® are vaccines against certain types of cancer- causing human papillomavirus (HPV – type 6, 11, 16, and 18) Cancer
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Cancer of the cervix uteri H P V Normal Early Stage IB Late Stage IB Stage IB
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HPV vaccines: SILGARD®: 0, 2, and 6 month i.m. (from 9 to 26 years old) CERVARIX® Cervarix® HPV
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Prof. G. Gorchev, MD, DSc: Medical University – Pleven
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 Radio-pharmaceuticals (radionuclides) - Irradiated with beta-rays): 131I, 32P (Sodium phosphate), 183Pal - palladium, 145Sm - samarium 89Sr (strontium)  Brahiterpiya (locally in prostate or vaginal cancer)  Photodynamic cancer therapy (irradiation with laser light, with consequent formation of free radicals): - Porfimer, Temoporfin VI. Radiotherapy
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VII. CANCER SUPPORTIVE THERAPIES
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Cisplatin Carmustine Cyclophosphamide Mitomycin C L-Asparginase Fluorouracil Methotrexate Etoposide Vincristine Emetogenic activity
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Colony-stimulating factors (CSFs) are used in special cancer therapy centers to reduce the severity and duration of neutropenia induced by cytotoxic anticancer chemotherapy; used in aplastic anaemia; used in anaemia in AIDS too.
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Molgramostim (Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor – rHuGM-CSF) Filgrastim (Recombinant Human Granulocyte Colony- Stimulating Factor – rHuG-CSF)
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“BURNOUT” syndrome
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www.medpharm-sofia.eu