Workshop 7 Antineoplastic Drugs 3° Medicine Aa 2024-25 PDF

WORKSHOP 7 Antineoplastic Drugs 3° Medicine Aa 2024-25 Professor: Vittoria Carrabs PhD  Cancer – uncontrolled multiplication and spread of abnormal forms of the body’s own cells throughout the body. Neoplasm – A massof tissue formed as aresult of A...

WORKSHOP 7 Antineoplastic Drugs 3° Medicine Aa 2024-25 Professor: Vittoria Carrabs PhD  Cancer – uncontrolled multiplication and spread of abnormal forms of the body’s own cells throughout the body. Neoplasm – A massof tissue formed as aresult of Abnormal Excessive Uncoordinated Autonomous and purposeless Proliferation of cells  Pathophysiology of Cancer Genesis of a tumour cell A cell becomes cancerous due to mutations in its DNA, mainly through two types of genetic changes: 1. Activation of proto-oncogenes: Proto-oncogenes normally regulate cell growth, division, and death. When mutated, they become oncogenes, driving uncontrolled cell growth and neoplastic transformation. 2. Inactivation of tumor suppressor genes: These genes usually prevent cells from becoming cancerous. When they lose function due to mutations, cells are more likely to undergo carcinogenesis, as the checks against abnormal growth are removed.  Pathophysiology of Cancer There are mainly four characteristics that allow us to recognise cancer cells from normal cells. They are: 1. uncontrolled proliferation 2. dedifferentiation and loss of function 3. invasiveness 4. metastasis.  Pathophysiology of Cancer 1.Uncontrolled proliferation Cancer cells avoid the mechanisms that normally regulate cell division and tissue growth. Changes in cellular systems such a: growth factor production cell cycle transduction resistance to apoptosis telomerase expression (which confers immortality to tumour cells) development of new local blood vessels (angiogenesis)  Pathophysiology of Cancer 2. Dedifferentiation and loss of function Tumor cells undergo dedifferentiation and loss of function, becoming less specialized and more prone to uncontrolled growth. This shift not only increases their ability to proliferate and spread but also disrupts the original tissue’s function, contributing to cancer progression and malignancy.  Pathophysiology of Cancer 3. Invasiveness Tumor cells can invade nearby tissues by breaching barriers like the basement membrane. They develop enhanced movement abilities, aiding in tissue infiltration. Tumor cells produce enzymes that break down the extracellular matrix, clearing paths for invasion. They evade immune detection, helping them survive and spread. These invasive traits enable tumor cells to reach and grow in distant body sites, a hallmark of cancer malignancy. (metastasis potential)  Pathophysiology of Cancer 4. Metastasis Formation Metastasis formation is the process by which cancer cells detach from the primary tumor, enter the bloodstream or lymphatic system, and travel to distant organs, where they establish new, secondary tumors, driving cancer progression and complicating treatment. Angiogenesis is the process through which new blood vessels form from pre- existing ones, essential for tumor growth and metastasis.  CANCER PATHOGENESIS Transformation Proliferation Metastasis Rang & Dale, Pharmacology 10ª Ed. 2022  ANTINEOPLASTIC THERAPY I. Drugs altering DNA Cytotoxics II. Drugs interfering with growth or surival of tumour cells Targeted therapies and immunotherapy III. Drugs activating the immune system  CANCER TYPES Carcinomes 80% of the tumors Leukaemia Epithelial cells: Bone marrow Cancer: lung, breast, colon, prostate, erythrocytes  anemia cancer and stomach... leucocytes  infections platelets  coagulation Sarcomes alterations Connective or conjunctive tissue: Lymphoma Muscles, bones, cartilages Lymphatic tissue Lymph nodes and lymphatic organs Prefix depending on the source cell Adeno= glandula Chondro= cartilague Erytro= red blood cell Lipo= fat Melano= pigmented cell Mio= muscular cell Osteo= bones Osteosarcoma Prostate Adenocarcinome  COMMON UNWANTED EFFECTS OF ANTINEOPLASTIC DRUGS Beau’s lines Inmediate (few hours): Nausea Precocious vomiting (days-weeks): Phlebitis Leukopenia Weeks-months Renal failure myelosuppression Anemia anaphylaxis alopecia aspermia Anorexia Stomatitis Hyperpigmentation Delayed fever Ulcerations Neuropathies (months-years) Hemorrhagic cystitis diarrhea Pulmonary fibrosis Sterility psychosis Cardiotoxicity Carcinogenesis Early menopause Osteoporosis  STRATEGIES FOR TREATMENT Chemotherapy and Surgery Radiotherapy targeted Immunotherapy therapies Immune system activation Destruction Growth inhibition What Is Chemotherapy - Macmillan Cancer Support - YouTube  PHARMACOTHERAPY TREATMENT - PRIMARY (only option) THERAPY - NEOADJUVANT (before surgery) - ADJUVANT (after surgery) a) Initial tests to determine if the patient has a certain mutation BIOMARKERS DETECTION b) Combination of several therapies to improve effect and avoid the appearance of resistance c) Minimize toxicity in normal tissue Active against the tumor Combination Multiple drugs With different mechanism of action Sequentially With different toxicities Treatment in cycles: intervals between doses (2-3 weeks) allow the recovery of normal tissues affected by toxic effects (bone marrow) Metronomic posology: low doses without rest periods (lower adverse effects and resistance) PERSONALIZED TREATMENTS CHEMOTHERAPY RESISTANCES  CHEMOTHERAPY RESISTANCES Primary or acquired resistances Tumor cells reduce cytotoxic drug accumulation by overexpressing P-glycoprotein, which actively pumps drugs out, leading to drug resistance Inefficient activation of the drug Rapid repair of lesions: alkylating agents Alteration of the target: Topoisomerase II –Doxorubicin Modification of the p53 gene and excessive expression of the Bcl-2 gene family (anti-apoptosis)  THERAPEUTIC STRATEGIES I. Alter DNA tumor cell Cytotoxic drugs Drugs that damage DNA Drugs affecting DNA synthesis and stability II. Alter signals involved in the growth and differentiation of tumor cells Targeted therapies Drugs interfering with hormone-dependent signals Drugs that alter signals dependent on specific tumor pathways III. Immune system activation Immunotherapy Facilitators of the immune response Immune checkpoint inhibitors T cell therapy Vaccines I. Alter DNA tumor cell CYTOTOXICS: act in the cell cycle I. Alter DNA tumor cell CYTOTOXICS: act in the cell cycle Phase specific In neoplasms with a high proportion of proliferative cells Fase S Fase M Phase unspeficic Golan, 2012 Inhibitors of DNA repair In neoplasms with a Olaparib high or low proportion of proliferative cells I. Alter DNA tumor cell Drugs that damage DNA 1 Nitrogen Mustards Ciclophosphamide 2 Nitrosureas: Carmustine, Lomustine ALKYLANTS 3 Others: Dacarbazine, Temozolamide I. Alter DNA tumor cell Drugs that damage DNA ALKYLANTS Mechanism of action These agents can cause cross-linking between DNA strands, which prevents the strands from uncoiling and separating, essential processes for DNA replication and transcription. They introduce alkyl groups into the DNA of cancer cells, which leads to DNA cross-linking and damage. ADRs: They bind to DNA molecules, typically at the N7 mutagenesis and position of guanine bases, forming covalent bonds that carcinogenesis, alopecia, alter the structure of the DNA. depression of bone marrow function and sterility  ALKYLANTS NITROGEN MUSTARDS MECLORETAMINA CYCLOPHOSPHAMIDE Oral administration Cit P450 Active metabolites that alkylate DNA by hepatic cytochrome P450 enzyme Monotherapy use and in combination with other drugs Broad spectrum: Non-Hodking lymphoma, breast and lung cancer Specific toxicity: Hemorrhagic cystitis Neurotoxicity Hepatic toxicity ALKYLANTS NITROGEN MUSTARDS METABOLISM OF Cyclophosphamide Aldophosphamide Phosphoramide Acrolein mustard Hemorrhagic cystitis Cytotoxic effect Mesna Mesna (mesna, 2-mercaptoethanesulfonate sodium) is a synthetic compound used as a chemoprotective agent to reduce the toxic side effects of cyclophosphamide. Damage DNA ALKYLANTS 2. NITROSUREAS 3. OTHERS CARMUSTINE TEMOZOLOMIDE LOMUSTINE liposolubility DACARBAZINE SNC USES Brain tumors DACARBAZINE use in malignant melanoma too  Damage Drugs that damage DNA DNA PLATINUM COMPOUNDS INTERCALATING AGENTS ↑↑emesis Ondansentron CISPLATIN Aprepipant CARBOPLATIN Intrastrand cross-links between neighboring guanine residues. Prevents DNA replication CLINICAL USES SPECIFIC TOXICITY Mannitol and Solid tumors: Nephrotoxicity sodium First-line drug for Ototoxicity treating testicular , ovarian , thiosulfate cervical, bladder, and lung cancers  Damage Drugs that damage DNA DNA ANTIBIOTICS -ANTRACICLINES INTERCALATING AGENTS DOXORUBICIN PHASE S AND G2 Mechanisms of action DNA intercalation  Decrease in the synthesis of DNA and RNA Generation of free radicals Inhibition of topoisomerase (no cells replication) Clinical uses: Specific TOXICITY Breast, bladder, ovarian cancer Cardiotoxicity Sarcomes Hyperpigmentation Carcinomes Hodking lymphome Untangler of Knots: The Amazing Topoisomerase Molecular Machine - YouTube  Drugs that damage DNA OTHER AGENTS NATURAL ORIGIN INTERCALATING AGENTS TRABECTEDIN IV administration Ecteinascidia turbinata Monotherapy: Tumor cells Immune cells Advanced sarcoma of soft tissues Macrophages Blood vessel Combined therapy: TRABECTEDIN With doxorrubicin, in platinum- sensitive recurrent ovarian cancer In tumor cells In macrophages Break of DNA (-) inflammatory and angiogenic mediators Arrest of cell cycle (-) Tumor angiogenesis  Drugs affecting DNA synthesis and stability PHASE S AND M More effectives in cells with a high proliferation rate Bone marrow ADRs in healthy cells Gonadal cells more proliferative Epithelial cells: G.I, skin, hair follicle, nails - Bone marrow depression (Myelotoxicity) - Fatigue (anemia) - Delay in children's growth -Sterility -Teratogenicity -Poor wound healing -Alopecia -Mutagenicity and carcinogenicity -Gastrointestinal disorders: Nausea and vomiting  Drugs affecting DNA synthesis and stability ANTIMETABOLITES Specific of Phase S Structural analogues of metabolites involved in the physiological processes of growth and division A) Folate Antagonists METHOTREXATE B) Pyrimidine antagonists 5-FLUOROURACIL CYTARABINE GEMCITABINE C) Purine Antagonists 6-MERCAPTOPURINE X 6-THIOGUANINE AZATHIOPRINE  Drugs affecting DNA synthesis and stability ANTIMETABOLITES Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA Folates synthesis synthesis and cell division.  Drugs affecting DNA synthesis and stability ANTIMETABOLITES A) Folate antagonists METOTREXATE (MTX) Mechanism of action: Inhibition of enzymes responsible for nucleotide synthesis (dihydrofolate reductase).Inhibtion of nucleotide synthesis prevents cell division.  Drugs affecting DNA synthesis and stability Does not ANTIMETABOLITES cross the BBB! A) Folate antagonists METOTREXATE (MTX) Specfic toxicity Myelosuppression Nephrotoxicty  Fibrosis / hepatic cirrhosis  Lung toxictiy  Neurological toxicity (adm. intratecal) Clinical Uses: combined therapy (broad spectrum) Intrathecal administration to prevent meningeal metastases during chemotherapy of acute lymphocytic leukemia Immuno-supressiveagent in Rheumatoid arthritis,Crohnsdisease, Psoriasis  Drugs affecting DNA synthesis and stability ANTIMETABOLITES B) Pyrimidine antagonists 5- FLUOROURACIL (5-FU) IV administration ADRs: Oral and gastrointestinal ulceration Hepatic damage Clinical uses: Colorectal, gastric, pancreatic, ovarian Topical application of fluorouracil is used to treat actinic keratoses and noninvasive skin cancers  Drugs affecting DNA synthesis and stability ANTIMETABOLITES B) Pyrimidine antagonists CYTARABINE (ARA-C) Inhibits DNA polimerase Drug of choice in inducing remission in acute myeloid leukemia  Drugs affecting DNA synthesis and stability ANTIMETABOLITES c) Purine Antagonists 6- MERCAPTOPURINE HGPRT Interference in synthesis of adenine and guanine ClinicalUses:Acute leukemia(ALL), Choriocarcinoma AdverseEffects:bonemarrow & GImainly Hepatic necrosis rarely, hyperuricaemia  Drugs affecting DNA synthesis and stability TOPOISOMERASE INHIBITORS Topoisomerase I Topoisomerase II Camptothecin Analogs Podophyllotoxins IRINOTECAN ETOPOSIDE TOPOTECAN TENIPOSIDE Antraciclines Both are particularly active Topoisomerase I: Topoisomerase II: during the S phase generally involved in essential for untangling (synthesis) to facilitate DNA relaxing supercoils DNA during replication and replication. during transcription. is especially important during cell division.  Drugs affecting DNA synthesis and stability TOPOISOMERASE INHIBITORS Topoisomerase I Topoisomerase II Camptothecin Analogs Podophyllotoxins IRINOTECAN ETOPOSIDE TOPOTECAN TENIPOSIDE Antraciclines IRINOTECAN: colorectal cancer after ETOPOSIDE: testicular carcinoma, lung fluorouracil therapy cancer, and non-Hodgkin lymphoma Lymphomas and breast, cervical, gastric, lung tumors TENIPOSIDE TOPOTECAN: glioma, sarcoma, and Acute leukemias lung and ovarian tumors. ADRs: myelosuppression  Drugs affecting DNA synthesis and stability MICROTUBULS INHIBITORS The alteration of microtubule function blocks M-phase cells.  Drugs affecting DNA synthesis and stability MICROTUBULE INHIBITORS: Tubulin polymerization inhibitors VINCA ALKALOIDS VINCRISTINE, VINBLASTINE ,VINORELBINE (oral) VINBLASTINE VINCRISTINE Lymphocytic leukemia Catharanthus roseus Hodgkin and non-Hodgkin lymphomas Solid tumors as neuroblastoma VINORELBINE: lung cancer, breast cancer, and ovarian cancer. ADRs: Myelosuppression Peripheral neuropathy Microtubule inhibitors ~pharmacology~ - YouTube  Drugs affecting DNA synthesis and stability MICROTUBULE INHIBITORS: Microtubule stabilizers TAXANS TAXOL, PACLITAXEL, DOCETAXEL Clinical Uses Advanced ovarian cancer Advanced breast cancer Specific toxictiy Neutropenia Neurotoxicity Taxus Brevifolia Bradicardy and fluids retention Alopecia Hypersensitivity NO EMETIC AGENTS!  Drugs inhibiting the repair of damaged DNA PARP INHIBITORS: OLAPARIB Poly(ADP-ribose) polymerases (PARPs) are multifunctional enzymes comprising 17 members. They are involved in essential cellular functions, such as DNA transcription and DNA repair. Mechanism of action Olaparib inhibits the enzyme PARP, preventing DNA repair in cancer cells with BRCA mutations, leading to tumor cell death. What is a PARP Inhibitor? | Dana-Farber Cancer Institute | Science Illustrated - YouTube  II. Alter signals involved in the growth or survival of neoplastic cells HORMONE-DEPENDENT SIGNALS Non-healing therapy: CYTOSTATICS Useful only in certain tumors expressing the hormone receptor: Breast cancer ER+ Tamoxifem (SERM) Fulvestrant (pure antagonist) Anastrozole (Aromatase inhbitors) Breast cancer ER+ and prostate cancer Leuprolide (Continuous administration of GnRH analoges) Prostate cancer Finasteride, Dutasteride (5- reductase inhibitors ) Flutamide (Antagonists of androgens receptors )  II. Alter signals involved in the growth or survival of neoplastic cells HORMONE-DEPENDENT SIGNALS Breast cancer ER+ ER+ receptor (Estrogen Receptor-Positive) is a cellular receptor for estrogen. The ER receptor is present in cells of various tissues but plays a central role in mammary gland cells. When estrogen binds to the ER receptor, it activates cell proliferation. Under normal conditions, this process is regulated, but in ER+ tumor cells, estrogen stimulation can increase uncontrolled cell growth and division. II. Alter signals involved in the growth or survival of neoplastic cells HORMONE-DEPENDENT SIGNALS ESTROGENIC RECEPTOR-DEPENDENT (ER+) BREAST CANCER TREATMENT 1. Selective modulators of estrogenic receptor (SERM) TAMOXIFEN Oral Partial agonist/Antag. In breast competition with estradiol to bind to estrogenic R Adverse effects: hot flashes, thromboembolisms, possible uterine cancer 2. Antiestrogens FULVESTRANT IM Pure antagonist ER Adverse effects: hot flashes, increased risk of osteoporosis 3. Aromatase inhibitors ANASTRAZOLE, LETROZOL Oral Reduce estrogen levels and reduce cell growth Testosterona estradiol aromatase Adverse effects: hot flashes, arthralgia 4. GnRH analogues: LEUPRORELIDE, GOSERELINE High and sustained doses: desensitizers of R block LH/FSH release. IM, monthly depot II. Alter signals involved in the growth or survival of neoplastic cells HORMONE-DEPENDENT SIGNALS PROSTATE CANCER TREATMENT 1. Antagonists androgenic receptor: FLUTAMIDE ORAL ADRs: gynecomastia, infertility... 2. Inhibitors of androgen production: ABIRATERONE ORAL Irreversible and selective inhibitor of 17α-hydroxylase. It inhibits testicular, tumor and adrenal cortex androgenic production. 3.GnRH analogues: LEUPRORELIDE, GOSERELINE High and sustained doses: desensitizers of R block LH/FSH release. IM, monthly depot  II. Alter signals involved in the growth or survival of neoplastic cells SPECIFIC TUMOR PATHWAYS They act on specific pathways or proteins overexpressed in certain tumors Nomenclature according to their activity: Kinase inhibidors: “TINIB” = Inhibitors of tyrosin kinases “RAFENIB” = Inhibitors of RAF kinases “CICLIB”= Monoclonal antibodies: SORAFENIB, GEFITINIB, RIBOCICLIB “MAB”: the letters preceding this ending indicate the origin of the antibody: o: mice Xi: chimeric zu: humanized u: human The two letters preceding the font indicate the location of the antibody target: c(i): cardiovascular system k(i) interleukin l(i): immune system t(u): tumor RITUXIMAB, TRASTUZUMAB, IBRITUMOMAB  ANGIOGENESIS INHIBITORS Inhibiting VEGFR: BEVACIZUMAB (colon cancer) Inhibiting tyrosin kinases activated by VEGF: VANDETANIB, SUNITINIB, SORAFENIB Inhibiting the production of bFGF and VEGF: TALIDOMIDE, LENALIDOMIDE VEGFR:vascular endothelial growth factor Journal of Thoracic Oncology 2021 16205-215DOI: (10.1016/j.jtho.2020.10.006) bFGF: basic fibroblast growth factor  III. Activation of the Immune System Immune checkpoint Facilitators of the Cell therapy with inhibitors Vaccines immune response T lymphocytes CTLA4: Tumor infiltrating Prepare with IFN, IL-2 T cells antigens IPILIMUMAB PD1: T-CAR Prepare with lymphocytes dendritic cells NIVOLUMAB, PEMBROLIZUMAB PDL-1: Immunotherapy in cancer harnesses the ATEZOLIZUMAB, body’s immune system to recognize and DURVALUMAB, attack cancer cells, enhancing the AVELUMAB immune response specifically against tumors. Immune Checkpoint Inhibitors - YouTube  PHARMACOLOGICAL TREATMENT TREATMENT EXAMPLES: Non-Hodgkin lymphomas Classic treatment Current treatment CHOP + RITUXIMAB * C = Ciclofosfamida * H = Doxorubicina·HCl + T-CAR * O = Vincristine (specific cases) * P = Prednisone X 6-8 cycles➔ Day 1: CHO (iv) Days 2-6: P (oral) 18 rest days TREATMENT EXAMPLES: Testis cancer BEP : bleomycine + etoposide+ cisplatine (3 cycles) PEI (cisplatine, etoposide, Phosphamide) (4 cycles)  PHARMACOLOGICAL TREATMENT Breast cancer Surgery Radiotherapy Chemotherapy Hormonal agents Other targeted therapies Hormone therapy+ chemotherapy HER-2 (EGFR2): Trastuzumab + chemotherapy Chemotherapy Docetaxel - Cyclophosphamide Epirubicin - Cyclophosphamide (EC) Triple negative(TN): Docetaxel No ER (estrogens receptors) Eribulin No RP (progestagents receptors) Paclitaxel no HER2 Doxorubicin - Cyclophosphamide (also known as AC) CLINICAL USES OF NEWER ANTICANCER DRUGS Monoclonal antibodies Trastuzumab: breast cancer (HER2) Bevacizumab: metastatic colon cancer (VEGF) Rituximab : non hodgkins lymphoma (CD-20) Panitumumab : metastatic colon cancer (EGFR) Alemtuzumab : Chronic lymphocytic leukemia (CD-52) Nivolumab: metastatic melanoma and squamous non-small cell lung cancer (PD1) Atezolizumab: non-small cell lung cancer, renal cell carcinoma and bladder cancer (PDL-1) How Monoclonal Antibodies Treat Cancer - YouTube Exercise 1 A patient with early-stage breast cancer has followed combined treatment with the following drugs: Cyclophosphamide, Fluorouracil, Docetaxel and Tamoxifen. a) Indicate the pharmacological group to which each of the drugs belongs and comment on its mechanism of action. b) Indicate any specific adverse effect to be expected from treatment with cyclophosphamide and tamoxifen Exercise 2 A 68-year-old woman visits her doctor concerned about a lump she has found in her breast. The patient is sent for a scan to ascertain the nature and diagnosis of the condition 1. What diagnostic factors distinguish a malignant from a benign growth? 2. Outline the mechanism by which metastasis occurs and the tissues in which secondary growths are most likely to occur 3. Indicate at least 4 drugs used in the treatment of breast cancer 4. For each agent, outline the rationale for its use and its mechanism of action in reducing tumour growth 5. What main side effects may the patient experience as a result of the chemotherapy? 6. What additional therapies may be co-administered to reduce some of these symptoms? Exercise 3 Pau Donés shared his diagnosis in mid-2015, when he had to cancel a tour in Spain, the United States and Latin America due to a surgical intervention. At that time, he told his followers that “cancer is like a ghost that appears without warning. That is why it is important to be vigilant. With cancer prevention is better than cure makes all sense ”, reported in 2015 the newspaper El País. In 2015, Pau Donés said that he had medical tests done because he was tired all the time and felt “a pain in his belly”. "In 20 days I went from a little discomfort to having surgery for colon cancer," he said in the video where he announced his condition. The tumor was removed in surgery and, then, it was unknown that it also had 14 lumps in the liver, according to the Spanish portal ABC. In 2016, Pau Donés announced that he had beaten cancer. However, in February 2017 he reported that the disease had returned. "I do a CT (tomography of the abdomen and pelvis) and hidden in the peritoneum they find a small tumor," he said then, reported ABC. Although colon cancer occurs most often in the elderly, anyone can get it. Some of the factors that can lead to it are obesity, diabetes, eating a lot of fat and little fiber or having problems with chronic intestinal inflammation. However, during confinement in Spain, days before his death, Donés announced that he would return to music and dedicated a song from his balcony to medical personnel in the fight against the coronavirus. After his death on Tuesday, the Jarabe de Palo website changed its usual appearance with one of Pau Donés' phrases: "Goodbye... but see you later." a) Which drug could have been effective for colorectal cancer? b) Indicate the mechanism of action or this drug c) Taking into account the mechanism of action, please, explain one mechanism tha could lead to the resistance to the treatment