Prof. RavisankarVignan Pharmacy collegeValdlamudiGuntur Dist.Andhra PradeshIndia.email@example.com
TREATMENT• BASIC TERMS• SYMPTOMS & DIAGOSIS• TYPES OF CANCER• Oncogens• How cancer arises• Genes controling cell cycle• Statistics• Different types of treatment• Classification of drugs• Log kill hypothesis• Cell specific non specific drugs• Resistances• Adverse reaction• Widely used and recent drugs• Synthesis
WHAT IS CANCER: it is a class of disease characterized by..Uncontrolled proliferation of cells.DedifferentiationLoss of funtionInvasion to local tissuesSpread or metastasis to other parts of thebody.
Cancer is not a single disease. It is a group of more than 200different diseases.Cancer may spread to other parts of the body.currently 1 in 4 deaths in USA are due to cancer. 1 in 17 deaths are due to lung cancer.An estimated 2,22,520 people diagnosed lung cancer in theUnited States in 2010.Lung cancer is the most common cancer in men.
Breast cancer is the most common cancer inwomen.Around 15 lakh new cases are diagnosed everyyear in india.A total of 15,96,670 new cancer cases and5,71,950 deaths from cancer are projected to occurin the United States in 2011.
INTRODUCTIONNeoplasmsTumorsOncogens and oncogenesOncogenesisOncology
The medical term for tumor (or) cancer is Neoplasm,which means a relatively autonomous growth (or)un corodinated cell proliferation of body tissue.The term Neoplasm means New growth & the processof cell proliferation is called Neoplasia.The branch of medicine which deals with the excessivestudy of neoplasm (tumor) and its developmentdiagnosis and treatment is called “Oncology.”
• For the first time Hippocrates coined the Greek wordKarkinos i.e. (crab/cray fish) for malignant breast cancer.(because enlarge or swollen veins around themresembled the limbs ofcrab).• The term cancer was translated from a Latin wordcarcino i.e. Crab by celsus.• Galen used ‘oncos’ to describe all tumors, the rootof the modern word ‘oncology’.
5 MAJOR TYPESThere are five broad groups that are used to classifycancer.Carcinomas are characterized by cells that cover internaland external parts of the body such as lung, breast, andcolon cancer.Sarcomas are characterized by cells that are located inbone, cartilage, fat, connective tissue, muscle, and othersupportive tissues.Lymphomas are cancers that begin in the lymph nodes andimmune system tissues.Leukemias are cancers that begin in the bone marrow andoften accumulate in the bloodstream.
• According to Guinness World Records, the biggest tumorever removed intact from the human body weighed inat 303 pounds (137.6 kg)and measured• 3 feet (1 m) in diameter.• The tumor, located on the right ovary, was removed in1991 during an operation performed by ProfessorKatherine O’Hanlan at Stanford UniversityMedical Center in California.
China’s elephant man grows world’sLargest tumor on face.(50 pounds)The man-with-no-face.
• The doubling time is the mean (“average”) intervalbetween successive mitoses.• It is a characteristic of the particular type of tumor cell.Doubling time varies markedly among various kinds oftumors.• Burkitt’s tumor = it is approximately 24 hours.• In acute leukemia = 2 weeks.• In breast cancer = 3 months.• In multiple myeloma = 6 to 12 months.• A tumor cell becomes detectable when the number ofcells reaches about 109to 10 10cells. This requires 30 to33 doubling times.• The neoplasm becomes lethal when the populationreaches about 5x1011to 5x1012cells, after 39 to 42
GENE CONTOLING CELL CYCLE•The principle difference between mature of normal tissue andtumors is …•The rate of cell replication i.e. proliferation for most normaltissues equals the rate of cell death (a balance is maintainedbetween cell renewal and cell apoptosis (programmed celldeath), where as in neoplasm proliferation exceeds the celldeath.
Occasionally due to carcinogens (cancer causing agents) one of theCell get mutated and does not respond to normal growth controlmechanisms.This mutated cell undergoes further mutations and transforms i.e.to Converts in to tumor cell which starts proliferating vigorously. This in turn results in amass of abnormal cells (tissues) called tumour Or neoplasm.
(As the tumor cellgrows it require aSteady supply ofaminoacid,carbohydrates,oxygen,nucleicacid bases,andgrowth factors.Vascular endothelialgrowth factor,fibroblast growthfactorInteractswithreceptorsstimulateLeading to the branchingAnd extention ofCapillaries process known asANGIOGENESISVascular growth factors are present in normal cells these are released when tissue hasbeen damaged. Angiogeness helps in the repair of injured tissues and is controlled byAngiogenisis inhibitors( angiostatin and thrombospondin)Unfortunately this balance is disturbed in tumour growth.Newly developing endothelial cellsRelease proteinstimulates
The agents (physical, chemical and biological) which causes cancer are calledcarcinogens.1 Physical agents: Uv and ionizing radiations (x-ray, gamma and alpha andbetarays cause cancer, uv rays of sunlight, nuclear fission. These radiationshavemutagenic effect.Ex: Leukaemias, skin, lung, breast, osteosarcoma, thyroid cancer.2. Biological agents:a. Bacterial agents: peptic ulcers and chronic gastritis and if these areb. left untreated for a long time leads to gastric cancer.c. Fungal agents: The fungus Aspergillus flavus releases aflatoxins in stored
a. Viral agents: Cervical cancer,Burkitt’s lymphoma,hairy celllukaemia,Haepatic carcinoma.3. Chemical agents: Alkylating agents, The acylating agents,Polyaromatic hydrocarbons, Aniline, arsenic, Anthracenes,dimethylsulphate,diepoxybutane,acetyl imidazole, dimethylcarbamyl chloride.4. Genetic factors: Genetic inheritance plays a key role in causingsome of the cancers (breast carcinoma,retino blastinoma.5. Diet and habits: People taking rich in fats, low fibre content andstored grains.
• AntineoplAstic Agents are the drugs which areused in to management of malignant disease (i.e. cancer)• Antineoplastic agents are also known as Cytotoxic agents.cancer is a very difficult disease to treat. This has beenbecause of lack of reliable diagnostic tests for the earlydetection and not having the compounds which will cureany form of cancer.• Anticancer drugs used in the treatment of malignantdisease when surgery or radiotherapy is not possible or hasproved ineffective. They are also employed as adjunct tosurgery or Radiotherapy. They are used as the initialtreatment as in laeukaemia.• Chemotherapy usually involves combinations of drugshavingdifferent targets or mechanisms of action.Traditionalanticancer
1.chemotherapy----------rapidly dividing cells (cancer as well asnormal cells)metastasised cancersleukemia and lymphoma2. Radiotherapy---------in combination with other therapiesiodine -131----thyroid canceriridium-192----breast cancer3. surgery----------------not metastasized cancersprostate,breast or testicular cancers4.Immunotherapy----- immune system made strong to fightagainst cancers5.Hormone therapy---killing cancer cells by altering hormone levelstamoxifen reduces estrogen levels killing breast cancer6. Gene therapy------replacing defective genes
• How is cancer diagnosed and staged?• . Physicians use information from symptoms and several other proceduresto diagnose cancer.This procedure is called a biopsy.Physicians will analyze your bodys sugars, fats, proteins, and DNA at themolecular level. For example, cancerous prostate cells release a higher level of achemical called PSA (prostate-specific antigen) into the bloodstreamthat can be detected by a blood test.Common tests include Common tests include the following: Biopsy of the tumor Blood tests (which look for chemicals such as tumor markers) Bone marrow biopsy (for lymphoma or leukemia) Chest x-ray Complete blood count (CBC) CT scan MRI scan (magnetic resonance imaging)Extracting cancer cells and looking at them under a microscope is the onlyabsolute way to diagnose cancer.
According to WHO10 Million deaths worldwidein 2010This year till now 7 millionDeaths and 12 million newcasesAccording to WHO10 Million deaths worldwidein 2010This year till now 7 millionDeaths and 12 million newcasesSTATISTICS
TREATMENT OF CANCER• Cancer can be treated by the following means:• 1. SurgeryRobotic radical prostatectomy for prostate cancer.(3-D) view of the surgical field, at a greatlyincreased magnification, up to 15 times greater than the human eye.2. Radiation therapy.• 3.Immunotherapy.• 4.Hormonal therapy.• 5.Antibiotics.• 6.Chemotherapy.Chemotherapy is the term applied for a wide range of chemicalsubstances i.e. drugs that are employed in the treating the cancer.These drugs may act by various mechanisms likeInterfering with the replication of DNA.Inhibiting the formation of important molecules which are needed forDNA formation and inhibiting the mytotic spindle.
4. Antimetabolites and analogsa)Actinomycins &dactinomycinb)AnthracyclinsDuanorubicindoxorubicinc)OthersBleomycinMitomycin
Alkylating agentsAlkylating agents ::1.Mustard drugs1.Mustard drugs: Mechlorethamine,: Mechlorethamine, Chlo ram bucil,Chlo ram bucil, Cyclo pho spho m ide ,Cyclo pho spho m ide ,Me lphalanMe lphalan Nitrogen mustards get their name because they are related to thsulfur-containing mustard gases used during First world War.cyclophosphomideLauncherCH3Missile(odour resembling mustard,garlic plant hence the name given)
Alkylating agentsContains ractive alkyl Groups.These compounds undergoesneibhobouring group reactions,Produce highly reactiveCarbonium ion intermeadiates Which form covalent bondsBy alkylation at 7thPosition ofguanine in each of The doublestarnds of DNA Causing crosslinking/mispairing. This interferes in the separationof strands and prevents mitosis orarrest cell replication.Alkylating agentsAlkylating agentsMechanism of actionAlkylation is defined as replacement of hydrogen on an atom by analkyl group.nu - H + alkyl-Y ---------- nu-alkyl + H++ Y-
Undergoes neibhobouring group reactions toform Stained 3 membered onium , ethyleneimminium ion orAziridinium ions,which react with guaninegroups on DNA To produce cross-linking.If second alkyl halide reacts withWater Cross linking is the major factor
CELL CYCLE SPECIFIC AND CELL CYCLE NON SPECIFICDRUGSCELL CYCLE SPECIFIC AND CELL CYCLE NON SPECIFICDRUGSCCS drugs are effective for high growth fractionmalignancieswhere asCCNS drugs for both low and high growth fractionmalignancies.
AdversereactIonAdversereactIonChemotherapeutic agents damage thetissues that are having growth fraction, thesesinclude cancers and also normal tissues such asbone marrow ,hair follicles, GI tract mucosa ,gonadsetc as a result of action on these tissues thefollowing adverse actions are commonly seen..1. bone marrow toxicity2. impaired wound healing3. alopecia4. damage to gastrointestinalepithelium5. sterility6. growth retardment in children7. teratogenecity.8. nausea, vomiting and diarrhoea
RESISTTANCEMechanism Drugs or Drug GroupsChange in sensitivity (or ↑ level) or ↓binding affinity of target enzymes orreceptorsEtoposide, methotrexate, vinca alkaloids,estrogen & androgen receptorsDecreased drug accumulation via ↑expression of glycoprotein transporters,or ↓ permeabilityMethotrexate, alkylating agents,dactinomycinFormation of drug-inactivating enzymes Purine & pyrimidine antimetabolitesProduction of reactive chemicals that“trap” the anticancer drugAlkylators, bleomycin, cisplatin.doxorubicinIncreased nucleic acid repair mechanisms Alkylating agents, cisplatinReduced activation of pro-drugs Purine & pyrimidine antimetabolites
ChlorambucilUses: Multiple myeloma, Lymphosarcoma,Lymphocytic leukemia, PolycythemiaveraOverian adenocarcinoma, Hodkin’s disease and in combination testicularcancer.Chlorambucil acts by cross linking of DNA which results in formation of alteredproteins leading to decrease in cell division that ultimately causes death of the cell.Malignant lymphomas.
synthesisSynthesis of 5-flurouracilFluoroxy trifluoro methaneIt is a solid, white, odourless, partially soluble in water,methanol, insoluble in diehtyl etherHaving melting point 282oC.Adverse /Toxic effects:Nausea, tiredness, diarrhoea, pigmentation of skin,mouth sores, anaemia.blurred visionLoss of appetite, rashes, hair thinning , dermatitis.Therapeutic uses5-Flurouracil is used for treating the following cancersBreast cancerLiverSkin cancerStomach, pancreatic cancer, colon and rectal cancer.Cancer of anus, bladder, cervix, endometrium, prostrate, ovaries, penis.5-
WIDELY USED DRUGSGeneric Name Brands®Companies Indications Sales $ billion2006 2007 2008PARituximab Rituxan Roche NHL, RA 4.7 5.015.6Trastuzumab Herceptin Roche Breast Cancer 3.14 4.4 4.8Bevacizumab Avastin Roche Colon Cancer 2.4 3.93 4.7ImatinibGleevecGlivecNovartisCML, GIST Chronic Myelogenous Leukemia,GI Stromal Tumors2.5 3.1 3.4Darbepoetin Aranesp Amgen Anemia 4.1 4.2 3.3Docetaxel TaxotereSanofiAventisBreast, Lung, Prostate, Gastric cancer 2.2 2.6 3.2G-CSF Neulasta Amgen Neutropenia 2.6 2.7 3.2HumanPapilloma VirusGardasil Merck Cervical Cancer 1.5 3.0ErythropoietinProcritEprex J&J Anemia 3.2 2.9 2.3Erythropoietin Epogen Amgen Anemia 2.5 2.6 2.3Anastrozole ArimidexAstraZenecaBreast Cancer 1.5 1.7 2.0BMS,
•The presence of acetyl group is very essential for vinblastine toexhibit it Anti cancer activity. When this is hydrolysed activitygets destroyed.2. When free hydroxyl grops were acetylated the drug lost itsAntimalignant activity.3.The potency of vinblastine reduces drastically when the doublebonds were initially hydrogenated and finally converted tocarbinol group via reduction.Uses1.Vinblastine has been used in combinationTherapies for the treatment of lymphomas,Testicular cancer and ovarian cancer.Hodgkin’s disease.
1. Campothecin analogsCamptothecin is an alkaloid which was isolated fromCamptotheca acuminata, used mainly for treating sarcoma andleukemia.Why research is going on?a) Has potent anti tumor activity but has seriousproblems with solubility and toxicity..b) very impressive biological activity.c) The target for development starts with IRINOTECAN which wasrecently approved by FDA for treatment of refractory colorectal cancerd) The aim for the developments is to synthesis water solublederivatives of 7-Ethyl-10-Hydroxy Camptothecin.
Smokers who smoke between 1 and 14 cigarettes a day have eight times the risk ofdying from lung cancer compared to non-smokers. Smokers who smoke more than 25cigarettes a day have 25 times this risk compared to non-smokersfactsYou can see how the lung lookswithout the effects of inhalation ofsmoke.Note black specks throughoutindicative of carbon deposits frompollution.Smokers lung with cancer. White areaon top is the cancer, this is what killedthe person. The blackened area is justthe deposit of tars that all smokerspaint into their lungs with every puffthey take.
ALTERNATIVES FOR ANTINEOPLASTICSCancer chemotherapy is now entering a new eraProgress in this era has arisen from a betterunderstanding of the cellular chemistry involved inparticular cancer cellsThe use of antibodies and gene therapy is anotherarea of research which shows huge potential.
Finally, one of the best ways of reducingcancer is …..• Firstly…Public education campaigns ---30% of cancers are caused by smoking,excessive drinking, and hazardous solvents• Secondly, another 30% of cancers are diet related,The benefits of eating high-fibre foods, fruit, and vegetables are clear• various research projects aimed at identifying the specific chemicals in thesefoods which are responsible for this protective property. For example, Dithiolthiones are a group of chemicals in broccoli, cauliflower, and cabbageone of which involves the activation of enzymes in the liver to detoxifycarcinogens• Genistein is a protective compound found in soy products• Asian populations have a low incidence of breast, prostate, colon cancers.• antioxidant present in green tea• Synthetic drugs are possible cancer preventives(finasteride, aspirin, ibuprofen, and difluoromethylornithine).
Anticancer agents are having severe adverseeffects and their usage should be limited and itis highly impossible to lead a happy life withcancer , The only best thing we can do is tomaintain a distance from carcinogens.
References1. Wikipedia2. William o.foye, textbook of medicinal chemistry3. 4. Text book of medicinal chemistry by ashutosh kar5. Text of pharmacology by rang and dale6. Text book of pharmacology by katsung7. Text book of biochemistry by rambabu
References• Wikipedia• William o.foye, textbook of medicinalchemistry• Wilson and gisvold`s text book of organicmedicinal chemistry and pharmaceuticalchemistry• Text book of medicinal chemistry by ashutoshkar• Text of pharmacology by rang and dale.• J.med.chem.,1996,39,3806-3813• EP-236940.• 10. J.org.chem.,46(5)846-851,1981.• J.Am.chem.soc.,48,2379(1926)• Chem.pharm.bull.,39,6-1446-1454(1991)