Introduction To Anti-cancer Drugs PDF

‫كلية الطب‬ College of Medicine Introduction to Anti-cancer (antineoplastic) drugs-I · · - Fadhel Ahmed Alomar, Ph.D. Associate Professor, Department of Pharmacology Office # M2013, [email protected], Phone: 0539200855 Lecture Objectives ❑ After studying this unit, YOU WILL BE ABLE TO …. 1....

‫كلية الطب‬ College of Medicine Introduction to Anti-cancer (antineoplastic) drugs-I · · - Fadhel Ahmed Alomar, Ph.D. Associate Professor, Department of Pharmacology Office # M2013, [email protected], Phone: 0539200855 Lecture Objectives ❑ After studying this unit, YOU WILL BE ABLE TO …. 1. Describe the hallmarks of cancer, cell cycle dysregulations in cancer and their relevance to tailor greatest therapies to individual cancer 2. Describe the role of cancer stem cells in the cancer relapse & metastasis 3. Explain the general concepts of anticancer agents and challenges associated with the treatment of cancer 4. Explain the mechanistic basis for primary (innate) and acquired resistance associated anticancer drugs 5. List and describe the short- & long-term toxicity, and the dose-limiting toxicities of anticancer agents 2 Pathophysiology of cancer FYI ❑ Example of gene mutations: -continue 2. An increase in the expression of oncogenes ➢ Oncogenes encode proteins that have the potential to cause cancer ➢ For example Abl gene (in the Philadelphia chromosome) → causes chronic myelogenous leukemia (CML, also called or chronic granulocytic leukemia; cancer of WBC) ❑ Problem: people can inherit this mutation e.g BRCA-1 & BRCA-2 mutation ❖ BRCA1/2, a human tumor suppressor genes, are responsible for repairing DNA ❖ When BRCA1 or BRCA2 is damaged by mutation, they will not repair the damaged DNA properly → ↑ the risk for breast & ovarian cancer The hallmarks of cancer cells and their related to pharmacology 1. Rapid uncontrol cell proliferation (growing) in absence of cell growth signaling ➢ The selective toxicity of many anti-cancers comes from they target rapidly proliferating cells 2. Acquired resistance to apoptosis- Inhibition of apoptotic machinery program 3. Stimulating angiogenesis (↑VEGF) ➢ ➢ Formation of a new blood vessels for nutrition & replication Bevacizumab drug inhibits angiogenesis 4. Invasion the surrounding cells ➢ There is no contact inhibition with neighboring cells 5. Metastases; the spread of a cancer from one place of the body to other places ➢ 6. In late stage, often deadly, & Difficult to treat (palliative treatment) Avoiding detection and destruction by the host’s immune system ➢ Dostarlimab blocks programmed cell death receptor-1 (PD-1) The hallmarks of cancer cells and their related to pharmacology ❑ Compared microscopically to normal cells, cancer cells are graded based on their appearance from well-differentiated to undifferentiated cancer cells (more aggressive) ❑ Normal cell can transform into cancer cell (malignant transformation) Malignant transformation Differentiated cancer cells can response to anticancer drugs With time, cancer cells lose their similarity to their mother cells and become more resistant to treatment Cancer stem cells (CSCs) FYI ❖ A unique subpopulation (~0.5 %) of the total cancer cells that have selfrenewal & generate heterogeneous lineages of cancer cells that comprise the malignant tumor ❖ Characterized by low rate of proliferation & high degree of resistance to anti- cancers → CSCs cannot be eliminated by the conventional anticancer ❖ CSCs are responsible for relapse & metastasis which are involved in more than 90% of all cancer death ➢ Development of novel strategies to eradicate CSCs are considered one of the HOT TOPIC IN CANCER RESEARCH to improve survival, particularly for patients with metastatic cancer General concepts of anti-cancer medications 1. The selective toxicity of anticancer medications come from they kill rapidly dividing (cancer) cells but not slowly (or non-) dividing normal cells 2. Problem: Cancer cell is self cell (not foreign cell) ➢ Although cancer cell is not identical, it is similar to normal cells → thus, (i) cancer cell evades immune recognition & (ii) limits potential targets for selective toxicity of anticancer drugs 3. Cancer cells are killed by first-order kinetics (constant fraction); reduce tumor cell burden to a point where the immune system can eradicate the remaining cancer (neoplastic) cells General concepts of anti-cancer medications Immune cells can eradicate the remaining cancer cells General concepts of anti-cancer medications 4. Different types of cancer behave differently, thus they require different treatment 5. Treatment is more effective if it is started at the early stage of cancer 6. Because of therapeutic window (TW) of anticancer is narrow, they potentially affect normal cells that routinely undergo cell division e.g the gastrointestinal tract (GIT) & bone marrow, thus I. In most cases, the dose should be calculated based on body surface area not age or body weight II. Rescue therapy are regularly given along with anticancer drugs to prevent or lessen the toxicity of cancer chemotherapy ✓ e.g erythropoietin is used to treat loss of RBCs General concepts of anti-cancer medications 7. A combination of anti-cancers from different classes is commonly used. e,g CHOP= Cyclophosphamide, hydroxydaunorubicin (a synonym of doxorubicin), vincristine (marketed under the brand-name Oncovin®) & prednisolone-FYI i. To enhance the efficacy ii. To prevent resistance development (multiple drug resistance, MDR) iii. To decrease the severity of adverse effects of anticancer drugs a. Each anticancer drug in the combination regimen should have a different MOA & act at different cell cycle phase specificity (if possible) b. Each anticancer drug also dose not have overlapping dose-limiting toxicity to avoid therapy failure (same serious S.E) Treatment options for cancer I. Surgery II. Radiation therapy III. Bone marrow transplantation IV. Pharmacotherapy 1. 2. Anticancer drugs (paclitaxel) Supportive & Palliative (symptomatic therapy) for N/V (ondansetron), diarrhea , pain, & others associated with cancer treatment Classification of anticancer (antineoplastic) drugs ❑ There are two major classes of anticancer agents I. The cell cycle specific (CCS) anticancer agents ➢ They attack cancer cells in a particular phase of the cell cycle II. The cell cycle nonspecific (CCNS) anticancer agents ➢ They attack cancer cells during G0 or any phase of the cell cycle The cell cycle specific (CCS) anticancer drugs ❑ ❑ Attack cancer cells in a specific phase of the cell cycle Are very effective against high growth fraction malignancies (leukemia) * in which Phase is (Drugname) is ? G2: Cells continue to grow & more ↑↑# of organelles e.g mitochondria to prepare cell for mitosis Synthesis (S) phase : DNA replication S-phase CCS anticancer drugs o Methotrexate & 5-fuorouracil G2 phase CCS anticancer drugs o Bleomycin Mitosis (M): Cell growth stops & cell undergo division into two daughter cells M phase CCS anticancer drugs (mitotic spindle inhibitor) o Vincristine o Vinblastine o Paclitaxel p53 Growth-1 (G1) phase : ↑ es # of organelles & ↑ size to prepare DNA for replication G1-phase CCS anticancer drugs o Tamoxifen & Lasparaginase Mitogenic signal G0 phase: Resting state, No growth The cell cycle non-specific (CCNS) anticancer drugs ❑ ❑ Attack cancer cells during any phase of the cell cycle Are effective against both low growth fraction malignancies (solid tumors) and high growth fraction malignancies The cell cycle nonspecific antineoplastic drugs (CCNS) o Alkylating drug & Cisplatin Problems associated with antineoplastic treatment I. Development of anticancer drugs resistance II. The adverse effects of anticancer drugs are unavoidable Development of anticancer resistance ❑ Definition of anticancer resistance ❖ Failure of cancer cells to undergo apoptosis in response to DNA damage or stress induced by anti-cancer drugs ❖ Cancer stem cells are one of the major contributor factors to development of anticancer drugs resistance ❑ There are two types of resistance I. Primary (innate) resistance II. Acquired resistance Development of antineoplastic resistance I. II. Primary (innate) resistance ❖ Cancer cells do not respond to anticancer therapy initially ❖ Studies have shown that primary resistance is associated with genomic instability ➢ p53 mutation (Tumor suppressor genes) are presented in about 50% of all cancers & more commonly in the colon & lung cancer Acquired resistance ❖ Cancer cells become resistant during treatment ❖ Several mechanisms involve to acquired resistance including, 1. Decreased drug transport into cancer cells e.g methotrexate (MTX) 2. Alteration (mutation) in the target enzyme, ↓ed affinity of DHFR e.g MTX) 3. Rapid repair of drug-induced DNA damage e.g cisplatin & alkylating agents 4. Overexpression of anticancer efflux proteins particularly, P-glycoprotein e.g doxorubicin →Multiple Drug Resistance (MDR) Multiple drug resistance (MDR) ❑ Usually, cancer patients with MDR are resistance to several unrelated anticancer drugs (other anticancer drugs) ❖ MDR results from increase expression of MDR1 gene encoding P-glycoprotein efflux transporter and others ❖ Usually, MDR occurs after prolonged use of low doses of anticancer drugs ❖ MDR can be prevented by using a combination of anticancer drugs for short term with intensive intermittent therapy Problems associated with antineoplastic treatment I. Development of anticancer drugs resistance II. The adverse effects of anticancer drugs are unavoidable General toxicity associated with anticancer drugs ❑ Almost all anticancer drugs have some degree of toxicity even within their therapeutic window ❑ Most normal cells have a low growth fraction, THUS they are not killed by anticancer agents except those have a high growth fraction (actively dividing ), e.g ❑ a. Bone marrow stem cells: anticancer drugs →Bone marrow suppression b. Hair follicles: anticancer drugs → reversible alopecia (short term toxicity) c. GIT: anticancer drugs → nausea & vomiting Toxicity of anticancer drugs can be divided into two major groups... I. Short-term toxicity II. Long-term toxicity Short-term toxicity of antineoplastic agents 1. Bone marrow suppression ❖ Reduction in RBC →causes anemia ❖ Reduction in platelet (thrombocytopenia) → increases risk of bleeding ❖ Reduction in WBC → increases risk of infection (life threatening) ❖ Rescue therapies for bone marrow suppression include, 1. Erythropoietin is used to treat loss of RBCs 2. Leucovorin factor is used to teat megaloblastic anemia (very large RBCs & reduction in the number of mature RBCs) induced by methotrexate (specific) 3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) administration is used to minimize or reverse bone marrow suppression adverse effects 4. Antimicrobial agents are used to prevent opportunistic infections like bacterial, candida and viral infections Short-term toxicity of antineoplastic agents 2. GIT toxicity: ❖ Nausea & vomiting (N/V) due to stimulation of chemoreceptor trigger zone & vomiting center in the medulla oblongata (no BBB) ❖ The administration of a combination of (1) ondansetron (5-HT3 receptor antagonist), (2) aprepitant (Neurokinin 1 receptor antagonist) and (3) dexamethasone before starting anticancer agents (as prophylaxis) is very effective treatment for chemotherapy-induce nausea and vomiting (CINV) is ❖ Diarrhea (due to epithelial cell damage)- Treatment is symptomatic ❖ Esophagitis, stomatitis (painful inflammation of the mucous membrane of the mouth) & proctitis (inflammation of the rectum and anus) Short-term toxicity of antineoplastic agents 3. Hyperuricemia (high uric acid levels in the blood) due to massive cancer cells kill by anticancer agents → DNA degradation → produces excess purine → purine is metabolized by xanthine oxidase XO in liver to uric acid → causes hyperuricemia → leads to Gout & urate stones in urinary tract ❖ Allopurinol drug (XO inhibitor) is used to prevent gout & renal injury-induced by anticancer agents 4. Blistering of skin results from extravasation of vesicants ❖ Cyclophosphamide (derived from nitrogen mustards) is an example of vesicant o ❖ Mustard gas was used in the World War I Vesicants cause severe local tissue damage around the site of IV administration if it escapes from the vein ✓ Discontinue the infusion, start at another site & applied 1% hydrocortisone Long-term toxicity of anticancer drugs 1. Lymphoma may develop years after anticancer drugs (secondary malignancy) 2. Sterility ❖ In males, impotence and oligospermia may persist for several years or be permanent ❖ in females, amenorrhea & inhibition of ovulation 3. Abortion may occur 4. Teratogenicity (dangerous) ❖ Woman should avoid becoming pregnant for 4 months after chemotherapy Drugs with unique dose limiting toxicity Anticancer Drug Toxicity 1 Cyclophosphamid e hemorrhagic cystitis 2 Cisplatin Nephrotoxicity (burning on urination) 3 Vincristine 4 Vinblastine Myelotoxicity (bone marrow suppression) 5 Bleomycin Lung pneumonitis & fibrosis 6 Doxorubicin Cardiotoxicity ( CHF: leg swelling & orthopnea) 7 L-asparaginase Hypersensitivity 8 Dostarlimab Immune-related adverse reactions (colitis) Neurotoxicity (finger numbness & tingling) Congestive heart failure (CHF) Tingling