Chemotherapy of cancer (malignancy) .pptx

Chemotherapy of malignancy (cancer)
introduction, classification, etiology, cause,adverse effect,use

1. Chemotherapy of cancer Nittal vekaria Roll no:48 K.B Institute Of Pharmaceutical Education & Research Guided by: Dr. Palak shah

2. What is cancer? Cancer is a group of diseases involving uncontrolled cell growth A normal cell turns into a cancer cell because of one or more mutations in its DNA, which can be acquired or inherited Cancer arises as a result of a series of genetic and epigenetic changes, the main genetic lesions being: Inactivation of tumor suppressor genes The activation of oncogenes (mutation of the normal genes controlling cell division and other processes)

3. Molecular basis of cancer (carcinogenesis)

4. Characteristics of cancer Cancer cells characteristics that distinguish them from normal cells; i . Uncontrolled proliferation ii. Dedifferentiation and loss of function(anaplasia) iii. Invasiveness (cancer spread beyond the layer of tissue ) iv. Metastasis

5. Normal vs abnormal Normal cell….. Cell growth abnormalities…. Differentiate Hyperplasia Grow Metaplasia Mature Dyplasia Divide Neoplasia –:abnormal growth of tissue (divided into two) Regulated Benign Balanced; cell birth= cell death 2) malignant

6. Types Site of origin with example Carcinoma Malignant neoplasm of epithelial origin or cancer of the internal or external lining of the body Example: Adenocarcinoma, which develops in an organ or gland, and Squamous cell carcinoma originates in squamous epithelium Sarcoma Cancer that originates in supportive and connective tissues such as bones, tendons, cartilage, muscle & fat Example : Osteosarcoma, Chondrosarcoma, Leiomyosarcoma, Rhabdomyosarcoma, Fibrosarcoma, Liposarcoma, Angiosarcoma , Myxosarcoma Myeloma Cancer of that originates in the bone marrow Example: Myelogenous or Granulocytic leukemia , Lymphatic, Lymphocytic, or Lymphoblastic leukemia , Polycythemia vera or erythremia Lymphoma Cancer that develop in the glands or nodes of the lymphatic system and organs (mainly the spleen, tonsils, and thymus) Example: Hodgkin lymphoma and Non- hodgkin lymphoma Mixed types Mixed cancers develop in different types of cell from one type or multiple types Example: Adenosquamous carcinoma, Aixed mesodermal tumor , Carcinosarcoma, Teratocarcinoma

7. characteristics Non- hodgkin’s disease Hodgkin’s disease Definition Cancer in which there is monoclonal proliferation of B or T lymphocytes Hodgkin lymphoma (HL) disease is lymph malignancy of proliferating germinal centre cell Distribution Non-contagious lymph node spread Contagious lymph node spread Histology Not pr. (Varies) Reed- sternberg cells incidence Increasing Stable site Non- hodgkin’s lymphoma develops in lymph nodes anywhere in the body Hodgkin lymphoma disease thypically begins in the upper body, such as the armpits, chest , and neck

8. Small cell lung cancer Non- small cell lung cancer   small cell lung cancer is a type of  lung cancer  arising from the neuroendocrine cells non-small cell lung cancer arises due to varied reasons and has three main varieties based on the origin; the  squamous cell carcinoma, adenocarcinoma  and large cell carcinoma . Small cell lung cancer is usually more aggressive Spread slowly Small size cell that grow and spread Large size cell that grow and spread

9. Etiology 1. Physical agents: UV and ionizing radiations ( x-ray, gamma and alpha and beta rays cause cancer, uv rays of sunlight , nuclear fission. These radiations have mutagenic effect. 2. Biological agents a) bacterial agents : peptic ulcers and chronic gastritis and if these are be left untreated for a long time leads to gastric cancer B) fungal agents : the fungus aspergillus flavus releases aflatoxins c) viral agents : cervical cancer, burkitt’s lymphoma, hairy cell leukemia , hepatic carcinoma. 3. Chemical agents: alkylating agents, the acylating agents, polyaromatic hydrocarbons, aniline, arsenic, anthracenes, dimethylsulphate , acetyl imidazole, dimethylcarbamyl chloride. 4. Genetic factors: genetic inheritance plays a key role in causing some of the cancers 5. Diet and habits : people taking rich in fats, low fibre content, smokeing , alcohol etc

10. 6. Oncogenes : an oncogene is a gene that has the potential to cause cancer. In tumor cells , they are often mutated or expressed at high levels 7. Tumor suppressor gene (p53):-  A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer.

11. Cell cycle G0-resting phase G1 - growth S - DNA synthesis G2 – growth and preparation for mitosis M – mitosis (cell division)

12. Diagnosis of cancer Cytology Histopathology Immunohistochemistry Molecular and cytogenetic diagnosis Flow cytometry Tumor markers Electron microscopy

13. Cancer therapeutic modalities Surgery : 1/3 of patients without metastasis respond to surgery and radiation. Radiation : if diagnosed at early stage close to 50% cancer could be cured. Chemotherapy : 50% patients will undergo chemotherapy, to remove micro- metastasis. However, chemotherapy can cure only about 10-15% of all cancer patients. Hormonal treatments: these drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division. Specific inhibitors : drugs targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells. Antibiotics : the antibiotics used in the treatment of cancer have been manufactured for use as drugs. Biological response modifiers : the use of naturally occurring, normal proteins to stimulate the body’s own defense against cancer. Vaccines : stimulate the body’s defenses against cancer. Vaccines usually contain protein found on or produced by cancer cells . by administering these proteins, the treatment aims to increase the response of the body against the cancer cells.

14. Malignancies which respond favourably to chemotherapy: 1 . Choriocarcinoma (woman’s uterus ) 2. Acute leukemia (blood, bone marrow) 3. Hodgkin’s disease 4. Burkitt’s lymphoma (non- hodgkin’s ) 5. Wilms’ tumor (kidney tumor ) 6. Testicular carcinoma 7. Ewing’s sarcoma (child) 8. Retinoblastoma in children 9. Diffuse histocytic lymphoma (digestive tract) 10. Rhabdomyosarcoma soft tissue sarcoma Antineoplastic drugs are most effective against rapidly dividing tumor cells

15. General toxicity associated with chemotherapy Nausea & vomiting Bone marrow depression (pancytopenia)- low no. of rbcs , wbcs , platelets Diarrhoea Immunosuppression Alopecia Delayed wound healing Oligozoospermia Carcinogenicity &mutagenicity Hyperuricemia Teratogenicity Neuropathy Cardiomyopathy ( acquired or hereditary disease of the heart)

16. Classification : 1. Alkylating agents Mechlorethamine Cyclophosphamide melphalan Ifosfamide Estramustine Chlorambucil Carmustine Lomustine streptozocin Busulfan Dacarbazine Procarbazine Altretamine Temzolamide thiotepa Bendamustine Dacarbazine

17. 2. Antimetabolites a. Folate antagonists B. Purine antagonist C. Pyrimidine analoguues Methotrexate Pemetrexate Pralatrexed Trimetrexate 6- thioguanine Azathioprine Fludarabine Mercaptopurine Pentostatin Cladribine Nelarabine Clofarabine Cytarabine 5- fluorouracil Floxuridine Gemcitabine

18. 3. Cytotoxic Antibiotics Doxorubicin Dactinomycin Bleomycins Daunorubicin Mitomycin c mitoxantrone Epirubicin idarubicin

19. 4. Natural products a)Vinca alkaloids b)Epipodophyllotoxins c) Camptothecins d) Taxanes Vincristine Vinblastine Vindesine Etoposide teniposide Topotecan Trinotecan Irinotecan Paclitaxel Docetaxel Cabazetaxel ixabepilone

20. 5. Hormones & their antagonists Glucocorticoids Prednisolone dexamethasone Estrogens Diethylstilbestrol Ethinyloestradiol Estrogen antagonists Tamoxifen Toremifen Fulvestrant Gonadotrophin release hormone (GnRH) agonists Goserelin leuprolide GnRH antagonist Cetrorelix Ganirelix abarelix androgens Testosterone fluoxymesterone progestins Hydroxyprogestrone Medroxyprogestrone Megestrol acetate Adromatase inhibitors Anastrozole Letrozole Exemestane

21. 6. Tyrosine kinase inhibitors Imantinib Lapatinib Dasatinib Sorafenib Nilotinib pazopanib Bosutinib Vandetanib Ponatinib Tepotinib 7. Monoclonal antibodies Trastuzumab Gemtuzumab Rituximab ozogamicin Bevacizumab Alemtuzumab Cetuximab 8. Platinum complex cisplatin Carboplatin oxaliplatin

22. 9. MISCELLANOUS Asparaginase :(ENZYME) Bexarotene Tretinoin Vismodegib Imiquimod

23. Classification of Anticancer drugs Cell cycle specific (CCS) drugs ; acts on proliferating cells, are most effective in hematologic malignancies and in solid tumors in which a relatively large proportion of the cells are proliferating Cell cycle- non specific (CCNS) drugs; can kill both G and cycling cells (although cycling cells are more sensitive). Are used in slow growing tumors

24. Cell cycle specific : G1 phase specific drug : L-asparaginase S phase specific drug: Anti-metabolites, topoisomerase II inhibitors M phase specific drug : Vinca alkaloids, taxanes G2 phase specific drug : Bleomycin , topoisomerase I blocker Cell cycle non specific : Active throughout the cell cycle :- Alkylating agents Platinum compounds Cytotoxic antibiotics

25. 1. Alkylating agents Cell cycle non specific Veno occlusive disease of liver ( budd-chairi syndrome)  defibrotide ( anti thrombotic) Secondary cancer - contain chemical groups that can form cross-bridge covalent bonds with DNA, as well as other nucleophilic substances in the cell Alkylating agents form carbonium ion cation, which is highly reactive and react instantaneously with an electron donor(nucleophile) such as an amine, hydroxyl or sulfhydryl group The major site of alkylation within DNA is the N7 position of guanine To a lesser degree N1 and N3 of adenine, N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA

26. Mechlorethamine Also known as mustine hcl M.O.A -:

27. IV FORMULATION : palliative treatment of:  Hodgkin’s disease (Stages III and IV)—combination MVPP (mechlorethamine, vincristine, procarbazine, prednisone)  Lymphosarcoma (non-Hodgkin’s)  Chronic myelocytic (bone marrow) or chronic lymphocytic leukemia ( wbcs  b cell)  Polycythemia vera  Mycosis fungoides (T-cell )  Bronchogenic carcinoma TOPICAL FORMULATION : indication for Skin-directed treatment for cutaneous T-cell lymphoma. Adverse effects: Anorexia , nausea, vomiting Bone marrow depression, aplasia ( Defective development) Menstrual irregularities Herpes zoster is frequently associated with treatment (shingles) Alopecia & skin rash

28. CYCLOPHOSPHAMIDE Cyclophosphamide, also known as  Mustargen Prodrug liver = aldophosphamidephosphoramideacrolein (cytotoxic action) cyclophosphamide aldophosphoramide chloroacetaldehyde phosphoramide mustard acrolein  Tablet formulation  Injection Formulatio n(iv)- 1 gm/5ml

29. Indication: DOC:- wegner’s granulamatosis Major role:- nephrotic syndrome, rheumatoid athritis -Malignant lymphomas (non- Hodgkin’s) -Hodgkin’s disease -Histiocytic lymphoma ( subtype of non-Hodgkin's lymphoma) -Multiple myeloma -Burkitt’s lymphoma(B-Cell lymphoma) -Autoimmune diseases( imunosuppresant )

30. Adverse effects Urinary tract haemorrhagic cystitis due to acrolein . So the patient should be well hydrated and treated by N-acetylcysteine or MESNA (sodium-2-mercaptoethanesulfonate-i.v,oral). Bone marrow depression Nausea and vomiting Alopecia and testicular atrophy chloracetaldehyde cause nephrotoxicity and neurotoxicity

31. melphalan  Oral formulation  Injection formulation (iv) -1gm/5ml Indication: -Multiple myeloma (Palliative treatment) -Epithelial carcinoma of the ovary Adverse effects: Mainly haematological toxicity Nausea and vomiting No alopecia (useful in woman)

32. Ifosfamide  Injectable solution (iv)- 50 mg/ml Indication: - Germ cell testicular cancer :used in combination with other antineoplastic agents for third-line therapy Off-label use: lung, breast, ovary, pancreas, bladder, and stomach cancer Adverse effect: Urinary cystitis Neuro toxicity—>methylene blue(antidote) Leukopenia, thrombocytopenia, myelosuppression Alopecia

33. Estramustine  Oral- capsule 140mg Indication: Prostate cancer (metastatic prostate ) Adverse effect: Cardiac arrest CHF Pulmonary emboli Thrombosis

34. chlorambucil  Oral dosage form Indication:- - Chronic lymphocytic leukemia - Non- Hodgkin’s lymphoma (NHL) and Hodgkin’s disese Adverse effects: Bone marrow suppression Carcinogenicity Mutagenicity and teratogenicity Human infertility

35. Carmustine  Intravenous wafers (each wafers contain 7.7 mg (3.85%) of carmustine Indication: -Brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, metastatic brain tumors ) - Multiple myeloma Hodgkin’s disease and non- hodgkin’s lymphomas Adverse effects: Bone marrow suppression, carcinogenicity, mutagenicity teratogenicity, human infertility Semustine  not use clinically due to renal failure

36. Lomustine Cross the bbb  Oral capsule (10mg, 40 mg, 100 mg) Indication : - brain tumors Hodgkin’s disease Adverse effects: Bone marrow suppression, carcinogenicity, mutagenicity teratogenicity, human infertility

37. Streptozocin - Chemical pancreatectomy agent  Injectable formulation (powder for injection ) Indication : Metastatic islet cell carcinoma of the pancreas Adverse effects: Renal toxicity Nausea & vomiting Liver dysfunction Diarrhea Hematological changes Mutagenicity & carcinogenicity

38. Busulfan  Oral formulation : 2mg to 20 mg  Injectable : 6mg/ml to 60 mg/ml Indication : Chronic myelogenous leukemia (cml).-affect the wbc (Currently the 1 st line doc for cml is emetinibe –tyrosine kinase inhibitor) Busulfan is used as part of a conditioning regimen prior to bone marrow transplantation. Adverse effects : Adrenal insufficiency Pulmonary fibrosis Prolonged myelosuppression

39. Dacarbazine Injectable form (iv) 200 mg Indication : - metastatic malignant melanoma Hodgkin’s disease (secondary-line therapy) Adverse effects: Hemopoietic depression Hepatic necrosis Carcinogenic & teratogenic effects

40. procarbazine Oral- capsule (50mg) Indication : Hodgkin’s disease (stage iii and stage iv ) - procarbazine is part of  copp (  cyclophosphamide ,  oncovin ,  procarbazine  and  prednisone )regimens. Glioma (brain tumor ) - Renal impairement Hepatic impairement Adverse effects Disulfiram like reaction(alcohol)  used by physician to leave alcohol Mao inhibitory action(cheese action) Hemopoietic depression Hepatic necrosis Carcinogenic & teratogenic effects

41. Altretamine It is hexamethyle melamine( hma ) Which act by alkylating DNA and protein  Oral – capsule (50 mg) Indication: Ovarian cancer Adverse effects Nervous system effects (seizure, fainting, severe dizziness) Allergic rxn ( hives, difficult breating ) Neurotoxicity

42. Temozolamide  Oral-(180 mg capsule) Indication : - newly diagnosed glioblastoma Anaplastic astrocytoma (CNS tumor ) Adverse effects: Seizures Chest pain or discomfort Wheezing and dry cough Low blood cell counts

43. Thiotepa  Injection (iv / intracavitary / intravesical instillation (bladder cancer ) ) Indication: -Stem cell transplantation - used as a conditioning treatment prior to allogeneic or autologous hematopoietic progenitor cell transplantation (HPCT) in hematological diseases  Solid tumors Brain tumor , malignant myeloma Breast cancer Bladder cancer Adverse effects: Nervous system effects (seizure, fainting, severe dizziness) Allergic rxn ( hives, difficult breating )

44. 2. Anti - metabolites These block or subvert one or more of the metabolic pathways involved in DNA synthesis Folate antagonists Folate are essential for the synthesis of purine nucleotides and thymidylate , which in turn are essential for DNA synthesis (s-phase of cell cycle ) and cell division Methotrexate  Inhibits dihydrofolate reductase + thymidylate synthase Dihydrofolate reductase converts the folate substrate (polyglutamates)first to Dihydrofolate (FH2), then to FH4 FH 4 , functions as an essential cofactor carrying the methyl groups necessary for the transformation of 2'-deoxyuridylate (DUMP) to the 2’ deoxythymidylate /deoxythymidine monophosphate (DTMP) required for the synthesis of purines and DNA

45. Mechanism of action :

46. Resistance Inhibit expression of DHFR Mutation of DHFR Poor activation Poor entry/ rapid efflux P-glycoprotein(inhibit) of cell cause efflux – verapamil use

47.  Oral formulation : tablet (2.5 mg, 5mg, 7.5mg, 10 mg, and 15 mg )  Injectable solutions (7.5mg, 10 mg, 12.5 mg,15 mg, 17.5 mg , 20 mg, 22.5 mg & 25 mg )  Pediatric oral solution : 2.5 mg per 1ml Indication : Doc:- choriocarcinoma - Abortion - Cancer treatment( acute lymphoblastic leukemia ) - Gestational trophoblastic neoplasia (ectopic pregnancy) - Autoimmune diseases(immunosuppression) :- rheumatoid arthritis , psoriasis, polyarticular juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE) Others: IBD: crohn’s disease, ulcerative colitis Adverse effects: bone marrow suppression, infection risk, renal toxicity, gastrointestinal toxicity, pulmonary toxicity, hypersensitivity reaction, dermatologic toxicity Embryo- fetal toxicity Neurotoxicity(intrathecally) Hepatotoxicity –long term use Contraindicated in pregnancy Leucovorin or folinic acid  antidote (except:-neurotoxicity)  glucarpidase –(increase metabolism of mtx metabolites excreted –liver)—not use together

48. Premetrexed -Lyophilized Formulation(100mg,500mg) Indication: -Malignant Pleural Mesothelioma -Non squamous Non-Small Cell Lung Carcinoma (NSCLC) Adverse effects: tarry stools, Bleeding gums, Chest pain, Chills, Cough, Fever, Loss of coordination, Lower back or side pain, Painful or difficult urination, Pale skin, Pinpoint red spots on the skin, Severe headaches of sudden onset, Sore throat, Sudden onset of slurred speech, Sudden vision changes, Swollen glands, Trouble breathing, Ulcers, sores, or white spots in the mouth, Unusual bleeding or bruising, Unusual tiredness or weakness

49. Trimetrexate Lyophilized formulation (100mg,500mg) Indication: -Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including those with AIDS. Adverse effects Abdominal pain or tenderness, Black tarry stools, Blood in urine or stools, Clay-colored stools, Dark urine, Decreased appetite, Fever and sore throat, Headache, Itching, Loss of appetite, Nausea and vomiting, Pinpoint red spots on the skin, Skin rash, Swelling of feet or lower legs, Unusual bleeding or bruising, Unusual tiredness or weakness, Yellow eyes or skin

50. Pralatrexate Injected (20mg/ml) i.v Indication: relapsed or refractory peripheral T-cell lymphoma (PTCL). Adverse effects (Arm, back, or jaw pain), (Black, tarry stools), Blood in the urine or stools, Chest pain or discomfort, Chest tightness or heavines , Constipation, Cough or hoarseness, Coughing or spitting up blood, Fast or irregular heartbeat, Fever or chill, General feeling of discomfort or illness, Lower back or side pain, Nausea, difficult urination, Pale skin, Pinpoint red spots on the skin, Shortness of breath, Sneezing, Sore throat, ulcers, white spots on the lips or in the mouth, Stomach pain, Sweating, (Swelling, Tender, swollen glands in the neck), Thickening of bronchial secretions, Troubled breathing, Unusual bleeding or bruising, Unusual tiredness or weakness, Vomiting of blood or material that looks like coffee grounds, Wheezing

51. (b) Purine antagonist Inhibits several enzymes for purine biosynthesis. Also forms metabolites like 6-methylmercaptopurine ribotide (MMPR) which contribute to its cytotoxic action. 6-mercaptopurine Oral formulation : tablet (50 mg) Oral suspension : 100mg/5ml 6-mercaptopurine hypoxanthine-guanine phosphoribosyl transferase (HGPRT)  deficiency ( Lesh-Nyhan syndrome) 6- thiosinic acid Indication : - Acute lymphocytic leukemia (ALL) - Others : acute promyelocytic leukemia (APL), autoimmune hepatitis, crohn’s disease, ulcerative colitis, lymphoblastic lymphoma Adverse effects : Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect

52. 6- thioguanine Mechanism of action : Like 6-MP, 6-TG is converted intracellularly to TGMP (6-thioguanylic acid) by the enzyme Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)  TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate and thioguanosine triphosphate  which inhibits the biosynthesis of purines and also the phosphorylation of GMP to guanosine diphosphate

53.  Oral formulation :tablet 40 mg  Oral liquid (suspension) Indication: -Acute myeloid leukemia -Acute lymphocytic leukemia -Chronic myeloid leukemia -IBD -Psoriasis Adverse effects: Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect

54. Azathioprine  Oral formulation (oral tablet:50 mg, 75mg, 100mg)  Injectable solution (100mg/vial) Indication : -Kidney transplantation (prevent rejection) -Rheumatoid arthritis -Lupus nephritis -Crohn disease -Ulcerative colitis Adverse effects : Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect

55. Fludarabine oral formulation 40 mg Systemic 25 mg i.v Indication: - B-cell chronic lymphocytic leukemia (CLL) Adverse effects: Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect

56. (c) pyrimidine antagonist : inhibiting thymidylate synthesis 5-fluorouracil Pro drug- capecitabine

57.  Injectable solution (500 mg/10ml, 2.5 g/50 ml, 5g/100ml)  Topical cream Metabolised in liver – co2 produced as metabolite excreted through lung(co2) Indication: -Cancer treatment ( colorectal cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer ) -Topical use : actinic keratosis ( a pre-cancerous skin condition due to sun exposure) , basal cell carcinoma, treating skin warts Adverse effects: Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect Hand foot syndrome Notes: Leucovorin increase the action of 5-FU

58. Cytarabine  injectable solution i.v (20mg/ml, 100mg/ml)  Intrathecal formulation Indication: -Acute non- lymphocytic leukemia (ANLL) -Meningeal leukemia Adverse effects : Bone marrow suppression, hepatic necrosis, carcinogenic & teratogenic effect

59. Gemcitabine INJECTION(lyophilized powder ) i.v 800mg /m 2 to 1250 mg/m 2 Incorporation into cytosine containing sites in the Growing strand Inhibits DNA synthesis Gemcitabine diphosphate  Inhibits ribonucleotide reductase   Se generation of deoxynucleoside triphosphates  se DNA synthesis

60. 3. Cytotoxic antibiotics Is a widely used group of drugs that mainly produce their effects through direct action on DNA As a rule, they should not be given together with radiotherapy, as the cumulative burden of toxicity is very high Doxorubicin - DNA intercalation, Doxorubicin forms complexes with DNA through G bases in both of the DNA strands and prevents Topoisomerase Ⅱ activity consequent in cell cycle disruption and cell death. - Topoisomerase II (a DNA gyrase); relaxes DNA super coils by nicking to facilitate DNA replication/during RNA transcription.

61. Injectable solution i.v (10mg, 20mg, 50mg,150mg,2mg/ml, 75 mg,100mg) Indication: -Cancer treatment(bladder cancer, breast cancer, lung cancer, stomach cancer, ovarian cancer, thyroid cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL) & acute myeloid leukemia (AML) Adverse effects : Myocardial damage Secondary Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS) Extravasation Severe Myelosuppression

62. DACTINOMYCIN (ACTINOMYCIN) Mechanism of action : - Intercalates in the minor groove of DNA between adjacent guanosine-cytosine pairs, interfering with the movement of RNA polymerase along the gene and thus preventing transcription. - It affects mRNA and protein synthesis. - Also has an effect on topoisomerase II.  Injection forms (iv) Indication: -Wilms tumor -Rhabdomyosarcoma -Ewing sarcoma -Gestational trophoblastic neoplasms -Testicular cancer

63. Adverse effects : Gastrointestinal effects ( Proctitis,Cheilitis , Dysphagia, Esophagitis, Ulcerative stomatitis, Nausea and vomiting, Abdominal pain, Diarrhea ) Hepatic effects Hematologic effects

64. Bleomycins - Are a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA - DNA-Bleomycin-Fe+2 complexes undergo oxidation, the released electrons react with oxygen to form superoxide or hydroxyl radicals which attack phosphodiester bonds causing chain fragmentation and release of free bases - Bleomycin is most effective in the G2 phase, but it is also active against non-dividing cells

65.  Injection (iv/ im / sc )-15 units and 30 units Indication: -Head and neck cancer -Testicular carcinoma -Pleural sclerosing (Pleurodesis)- excess fluid in pleural space in lungs Adverse effects: Pulmonary toxicity Idosyncratic reaction: Hypotension Mental confusion Fever Chills Wheezing

66. Daunorubicin( rubidomycin ) Binding to DNA and inhibiting the production of proteins necessary for sustaining life of a cell  Injection form (iv) Indication: -Acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) Adverse effects: Myocardial damage Secondary Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS) Extravasation Severe Myelosuppression

67. Mitomycin c Antineoplastic action : cross-linking of DNA &  DNA synthesis cell cycle arrested in G1-S Phase Anti-inflammatory action : inhibits proliferation of fibroblasts modulates wound healing & scarring local application, use in ENT  Injection ( i.v ) 5mg,20mg,40mg Indication : -Stomach and pancreatic cancer -Bladder cancer Adverse effects: Bone Marrow Suppression, Hemolytic Uremic Syndrome (HUS)

68. Mitoxantrone -affects dividing and non- dividing cells via inhibition of DNA synthesis and repair DNA intercalation - DNA topoisomerase II inhibition  Injection (iv) Indication : -Stomach and pancreatic cancer -Bladder cancer Adverse effects: cardiotoxicity

69. 4. Plant derivatives Vinca alkaloids Are derived from the Madagascar periwinkle. The principal members are vincristine , vinblastine and vindesine . The drugs bind to tubulin and inhibit its polymerisation into microtubules, preventing spindle formation in dividing cells and causing arrest at metaphase. Their effects become manifest only during mitosis.

70. Vincristine also known as  leurocristine , is an antineoplastic antibiotic   Vincristine sulfate injection (1mg) Indication : -Acute lymphocytic leukemia -Hodgkin’s lymphoma - wilm’s tumor -Neuroblastoma -Rhabdomyosarcoma Adverse effects : Blurred or double vision, Constipation, Difficulty walking, Drooping eyelids, Headache, Jaw pain, Joint pain, Lower back or side pain, Numbness or tingling in fingers and toes, Pain in fingers and toes, Pain in testicles, Stomach cramps, Swelling of feet or lower legs, Weakness

71. Vinblastine  Injectable solution (1 mg/ml, 10 mg) Indication: -Hodgkin’s disease -Lymphomas -Testicular cancer -Breast cancer -Choriocarcinoma -Kaposi’s sarcoma (lesions  soft tissue) -Letterer siwe disease (skin lesions, enlarged liver, spleen & lymph nodes, anemia , bleeding tendencies) Adverse effects: (Black, tarry stools), Blood in urine or stools, Cough or hoarseness accompanied by fever or chills, Pinpoint red spots on the skin, Unusual bleeding or bruising

72. b) Taxanes Derived from the bark of the yew tree (Taxus brevifolia ).   They bind on microtubules , stabilising them (in effect 'freezing' them) in the polymerised state, and act as poison for spindle formation leading to mitosis arrest. Paclitaxel ( taxol )  Injection i.v (30 mg,100mg, 300mg) Indication : - Breast cancer - Ovarian cancer - Lung cancer - Aids related Kaposi’s sarcoma Adverse effects: Anaphylaxis and Severe Hypersensitivity Reactions, Anaphylaxis and Severe Hypersensitivity Reactions

73. M.O.A INDICATION ADVERSE EFFECTS Docetaxel Docetaxel inhibits microtubule disassembly, promoting microtubule stabilization and blocking cell division, leading to apoptosis in rapidly dividing cells. Breast cancer Non-small cell lung cancer (NSCLC) Gastric cancer Head and neck cancer Bone marrow suppression Hypersensitivity reactions Fluid retention and edema Neurotoxicity Gastrointestinal effects Hepatotoxicity Myelosuppression cabazitaxel inhibiting microtubule depolymerization, leading to cell cycle arrest and apoptosis in cancer cells. metastatic castration-resistant prostate cancer ( mCRPC ) Bone marrow suppression Hypersensitivity Gastrointestinal effects Neurotoxicity Fatigue Fluid retention and edema Hepatotoxicity Myelosuppression Ixabepilone inhibits microtubule dynamics by binding to tubulin, leading to cell cycle arrest and apoptosis in cancer cells. metastatic or locally advanced breast cancer, particularly in patients who have previously received anthracycline and taxane chemotherapy regimens. Bone marrow suppression Peripheral neuropathy Hypersensitivity reactions Gastrointenstinal effects Fatigue Myalgia and arthralgia Hepatotoxicity

74. c) Epipodophyllotoxin Epipodophyllotoxin are cell cycle specific with activity in late S & G2 phase. Topoisomerase II creates and reseals double-stranded DNA breaks and therefore it is involved in DNA replication and repair. Epipodophyllotoxin inhibit topoisomerase II by stabilizing topoisomerase II -DNA complex & prevent the unwinding of DNA.

75. Etoposide Injectable solution (iv) (100 mg, 500mg,1g) Oral capsule (70 mg , 100 mg) Indication: - Small cell lung cancer (SCLC) Other malignancies - Other (Lymphoma, Non-lymphocytic leukemia , Glioblastoma multiforme, Gestational trophoblastic disease, Merkel cell cancer, Neuroblastoma, Neuroendocrine tumor , Ovarian cancer, Prostate cancer, Retinoblastoma, Wilm’s tumor , Advanced Hodgkin lymphoma, Ewing’s sarcoma Adverse effects: Severe Myelosuppression

76. (d) Camptothecins camptothecins are natural products derived from the Camptotheca acuminata tree originally found in China; they inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA damage. INDICATION ADVERSE EFFECTS topotecan Metastatic ovarian cancer Small cell lung cancer (SCLC) Bone marrow suppression Gastrointestinal effects Hypersensitivity reactions Fatigue Hepatotoxicity Myelosuppression-related infections irinotecan Metastatic colorectal cancer Advanced or metastatic non-small cell lung cancer (NSCLC) Metastatic small cell lung cancer (SCLC) Advanced or metastatic ovarian cancer Bone marrow suppression Gastrointestinal effects Hypersensitivity reactions Fatigue Hepatotoxicity Myelosuppression-related infections

77. 5. Hormones & their antagonists - Hormone-dependent tumors have steroid receptors in the malignant cells. - Their growth can be inhibited by hormones with opposing actions, by hormone antagonists or by agents that inhibit the endogenous hormone synthesis. - Hormones or their analogues that have inhibitory actions on target tissues can be used in treatment.

78. (a) Glucocorticoids eg : prednisolone, dexamethasone (po) Synthetic corticosteroid with less mineralocorticoid activity. • Used in Lymphomas associated with Cushing syndrome. • Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin’s and non-Hodgkin's lymphomas.

79. (b) Estrogen  Diethylstilbestrol and ethinyloestradiol used clinically in the palliative treatment of androgen-dependent prostatic tumours . However, they have been largely replaced by the GRH analogues because of fewer adverse effects.  Estrogens inhibit the growth of prostatic tissue by blocking the production of LH in the pituitary gland, thereby decreasing the synthesis of androgens in the testis. (c) Estrogen antagonist eg : tamoxifen, Tormifen , fulvestrant  First-line therapy in the treatment of estrogen receptor positive breast cancer Estrogen competes with tamoxifen.  Therefore, in premenopausal women, the drug is used with a gonadotropin-releasing hormone (GnRH) analog such as leuprolide, which lowers estrogen levels.  Cell cycle nonspecific agent.

80. Advere effects : Hot flashes, nausea, vomiting, skin rash, vaginal bleeding, and discharge (due to some slight estrogenic activity of the drug and some of its metabolites). • Hypercalcemia • Cause endometrial cancer. (d) Gonadotrophin-releasing hormone analogues eg : leuprolide and goserelin  The synthetic non peptides, Leuprolide and Goserelin are analogs of GRH. • GRH agonists, bind to GRH receptor in the pituitary, which leads to desensitization and, consequently, inhibition of release of FSH and LH.  • Androgen and Estrogen syntheses are reduced

81. Leuprolide used in Prostatic cancer. • These drugs have some benefit in premenopausal women with advanced breast cancer and have largely replaced estrogens in therapy for prostate cancer. • Leuprolide is available 1) as a sustained-release preparation 2) subcutaneous 3) as a depot intramuscular injection to treat metastatic carcinoma of the prostate. • Goserelin acetate is implanted intramuscularly. Goserelin

82. (e) Gonadotrophin-releasing hormone antagonist DRUGS M.O.A INDICATION ADVERSE EFFECTS Cetrorelix -Competes with natural Gnrh for binding to membrane receptors on pituitary cells   it controls the release of LH and FSH in a dose-dependent manner  binds to the Gnrh receptor and acts as a potent inhibitor of gonadotropin secretion Inhibition of premature LH surges in women undergoing controlled ovarian stimulation during assisted reproductive techniques. - It ensures that eggs are not prematurely released before they are ready for fertilization. Ovarian hyperstimulation syndrome (OHSS) Allergic reactions Ectopic pregnancy Multiple pregnancies Others : ovarian torsion (twisting of the ovary), ovarian cysts, and in rare cases, thromboembolism (blood clots). Ganirelix Same as above Prostate and breast cancer Hormonal imbalance Bone density loss Cardiovascular effects Liver toxicity Abarelix Same as above Advanced prostate cancer Hypersensitivity rxn Bone density loss : Liver toxicity Endocrine effects Injection site reactions Gastrointestinal effects

83. (f) Anti- androgen : eg : flutamide, nilutamide , bicalutamide) These drugs compete with the natural hormone for binding to the androgen receptor and prevent its translocation into the nucleus. - Antiandrogens are taken orally.  Used in the treatment of prostate cancer. Adverse effect gynecomastia and GI distress and, in the case of flutamide, liver failure could occur. Nilutamide can cause visual problems.

84. (g) Androgens eg : testosterone, fluoxymesterone Stimulation of androgen receptors  promotion of cancer cell growth  Hormone deprivation therapy ( Gnrh agonists or antagonists)  induction of apoptosis Used in prostate cancer Adverse effects : Cardiovascular events muscle loss and weakness Osteoporosis and bone fractures cognitive changes Metabolic changes Sexual dysfunction Hot flashes and fatigue Depression and mood changes

85. (h) Progestin eg : hydroxyprogestrone , medroxyprogestrone , megestrol acetate  megestrol acetate was formerly the progestin used most widely in treating metastatic hormone responsive  Breast and endometrial neoplasms  It is orally effectiv e (I) aromatase inhibitors eg : anastrazole , letrozole, exemestane  aromatase inhibitors block the enzyme aromatase, which converts androgens into estrogens. By reducing estrogen levels, they inhibit the growth of hormone receptor-positive breast cancer cells, slowing down tumor progression.

86. 6. Tyrosine kinase inhibitors It is an enzyme which add phosphate group (take phosphate group ATP and put it on protein  ADP  Phosphorylated protein (“signal transduction” )on-off switch molecular target BCR-ABL M.O.A :- block ATP binding to tyrosine kinase active site ATP PROTEIN P TK

87.   M.O.A Indication Adverse effects imantinib       inhibits the activity of specific tyrosine kinase enzymes, particularly BCR-ABL, C-KIT, and PDGF-R, thereby blocking signaling pathways involved in the growth and proliferation of cancer cells. Chronic Myeloid Leukemia (CML) Acute Lymphoblastic Leukemia (ALL) Gastrointestinal Stromal Tumors (GIST) Dermatofibrosarcoma Protuberans (DFSP) Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Bone marrow suppression Cardiotoxicity Hepatotoxicity Fluid retention Gastrointestinal effects Skin reactions Hemorrhage Interstitial lung disease Dasatinib inhibits multiple tyrosine kinases, including BCR-ABL, c-KIT, and SRC family kinases, disrupting signaling pathways involved in cancer cell proliferation, survival, and metastasis. Chronic Myeloid Leukemia (CML) Philadelphia Chromosome-Positive  Acute Lymphoblastic Leukemia (Ph+ ALL) Accelerated Phase Chronic Myeloid Leukemia (CML) in Children Bone marrow suppression Fluid retention Pulmonary arterial hypertension (PAH) QT prolongation Bleeding Hepatotoxicity Skin reactions Nilotinib inhibits the activity of the BCR-ABL tyrosine kinase, thereby blocking signaling pathways involved in the growth and proliferation of cancer cells. Chronic Myeloid Leukemia (CML) Philadelphia Chromosome-Positive  Acute Lymphoblastic Leukemia (Ph+ ALL) Cardiovascular events Pulmonary arterial hypertension (PAH) Bone marrow suppression Pancreatitis Hepatotoxicity Electrolyte abnormalities Fluid retention    

88. Bosutinib inhibits the activity of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, disrupting signaling pathways involved in cancer cell proliferation and survival. Chronic Myeloid Leukemia (CML) Liver toxicity Fluid retention Cardiovascular events Gastrointestinal effects Myelosuppression Pulmonary arterial hypertension (PAH) Skin reactions ponatinib inhibits BCR-ABL tyrosine kinase, including the T315I mutation, as well as other tyrosine kinases, suppressing aberrant signaling pathways associated with cancer cell growth and survival. Chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Cardiovascular events: Hepatotoxicity Pancreatitis Fluid retention Hypertension Thrombocytopenia Myelosuppression Skin reactions:

89. 7. Monoclonal antibodies Are immunoglobulins, of one molecular type, produced by hybridoma cells in culture, that react with defined target proteins expressed on cancer cells In some cases, binding of the antibody to its target activates the host's immune mechanisms and the cancer cell is killed by complement-mediated lysis or by killer cells Other attach to and inactivate growth factor receptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis Trastuzumab Rituximab Bevacizumab Cetuximab 5. Alemtuzumab

90. Trastuzumab In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor receptor protein 2 (HER2) is seen in 25 to 30 percent of patients. • This drug targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity. • Used in breast cancer • S phase specific Mechanism of action: Down-regulation of HER2-receptor expression, an induction of antibody-dependent cytotoxicity, or a decrease in angiogenesis due to an effect on vascular endothelial growth factor. Administered IV

91. Adverse effects Congestive heart failure Infusion-related fever and chills Headache Dizziness Nausea, Vomiting Abdominal pain Back pain Rituximab used (in combination with other chemotherapeutic agents) for treatment of certain types of lymphoma. It lyses B lymphocytes by binding to the calcium channel-forming CD20 protein and activating complement. It also sensitises resistant cells to chemotherapeutic drugs  Alemtuzumab is another monoclonal antibody that lyses B lymphocytes, and is used in the treatment of resistant CLL

92. 8. Platinum analogues eg : cisplatin, carboplatin,oxaliplatin (2 nd generation) - Non cell cycle specific drug. • It acts by forming high reactive platinum complexes which reacts with nucleophilic site of DNA and damages the DNA. Note : a copper transporter =CTR1 is involved in entry of platinum complex into tumour cells Adverse effects Emetogenic, nephrotoxicity, ototoxicity. Indication: - Testicular, ovarian cancer

93. 9. Miscellaneous agent Crisantaspase ; is a preparation of the enzyme asparaginase  It breaks down asparagine to aspartic acid and ammonia, active against tumour cells that have lost the capacity to synthesize asparagine and therefore require an exogenous source, such as those of ALL. The drug has a fairly-selective action

94. M.O.A INDICATION ADVERSE EFFECTS Bexarotene (oral-capsule ) 75 mg to 300 mg cutaneous T-cell lymphoma Hyperlipidemia Hypothyroidism Pancreatitis Leukopenia and Neutropenia Hepatotoxicity Birth Defects Photosensitivity Tretinoin (Topical ) 0.01% TO 0.1% 1. Promotion of Cell Turnover 2. Normalization of Keratinization 3. Anti-inflammatory Effects 4. Induction of Differentiation Acute Promyelocytic Leukemia (APL) Skin Irritation Photosensitivity Reactions Exacerbation of Acne Contact Dermatitis Hypopigmentation or Hyperpigmentation teratogenicity

95. M.O.A INDICATION ADVERSE EFFECTS Vismodegib Oral-capsule (150 mg) inhibiting the hedgehog signaling pathway  plays a crucial role in regulating cell growth and differentiation during embryonic development and tissue repair.  inhibits a key component of this pathway, called the smoothened (SMO) receptor  blocking downstream signaling and inhibiting the growth of hedgehog-dependent tumors Basal Cell Carcinoma (BCC) Muscle spasms Severe skin reactions Musculoskeletal adverse event Hepatotoxicity Cardiovascular events Hair loss Weight loss Embryofetal toxicity Imiquimod (Topical) Activating the body's immune response through Toll-like receptor 7 (TLR7) - macrophage,monocytes,dentritic cell - production of cytokines and enhancement of antigen presentation actinic keratosis superficial cancers Severe Skin Reactions Local Skin Reactions Skin Hypopigmentation or Hyperpigmentation Localized Infections

96. Newer Therapy

97. Anti-metabolites

98. Natural products

99. Miscellanous

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