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ANTICANCER DRUGS. BY Mr. Yasar Qazi. 1. CHEMOTHERAPEUTIC DRUGS. 2. 1. INTRODUCTION/DIFINTION.
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ANTICANCERDRUGS BY Mr. YasarQazi 1
1.INTRODUCTION/DIFINTION Cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis. Metastases are the major cause of death from cancer. (WHO) Cancer known medically as a malignant neoplasm, is a broad group of diseases involving unregulated cell growth. In cancer, cellsdivide and grow uncontrollably, forming malignant tumors, and invading nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream. Not all tumors are cancerous; benign tumors do not invade neighboring tissues and do not spread throughout the body. There are over 200 different known cancers that affecthumans. 3
3. RISKFACTORS 1.Tobacco 2.Sunlight 3.Ionizingradiation 4.Certain chemicals and other substances 5.Some viruses and bacteria Certain hormones Family history ofcancer 8.Alcohol 9.Poor diet, lack of physical activity, or beingoverweight 5
4. CHARACTERISTIC OFCANCER Cancer arises as a result of a series of genetic and epigenetic changes, the main genetic lesionsbeing: • • inactivation of tumour suppressorgenes the activation of oncogenes (mutation of the normal genes controlling cell division and otherprocesses). Cancer cells have four characteristics that distinguish them from normalcells: • • • • uncontrolledproliferation loss of function because of lack of capacity to differentiate invasiveness the ability to metastasise. Cancer cells have uncontrolled proliferation because of changesin: • • growth factors and/or theirreceptors intracellular signalling pathways, particularly those controlling the cell cycle and apoptosis telomerase expression tumour-relatedangiogenesis • • 6
5. THE SEVEN WARNING SIGNS OFCANCER The American Cancer Society uses the wordC-A-U-T-I-O-Nto help recognize the seven early signs ofcancer: Change in bowel or bladderhabits Asore that does notheal Unusual bleeding ordischarge Thickening or lump in the breast, testicles or elsewhere Indigestion or difficulty swallowing Obvious change in the size, color, shape, or thickness of a wart, mole, or mouth sore 7.Nagging cough or hoarseness 7
6. CANCERTYPES categorized based on the functions/locations of the cells from which theyoriginate: Carcinoma:a tumor derived from epithelial cells, those cells that line the surfaceof our skinandorgans(80-90%ofallcancercases reported) Sarcoma:a tumor derived from muscle, bone, cartilage, fat or connective tissues. Leukemia:a cancer derived from white blood cells or theirprecursors. Lymphoma:a cancer of bone marrow derived cells that affects the lymphaticsystem. Myelomas:a cancer involving the white blood cells responsible for the production of antibodies (Blymphocytes) 8
7. CELLCYCLE 2-5hrs 6-8 hrs 8hrs ormore Go – Resting p a Restrictioncheckpoint h se 10 Dr.K.Saminathan.M.Pharm, M.B.A,Ph.D
8.CARCINOGENESIS Acquired (environmentalDNA damaging agents) Chemicals Radiation viruses NormalCell Successful DNArepair DNADamage Failure of DNArepair Mutations in the genome of somaticcells Activation of growthpromoting oncogene Alteration of genes that regulatesapoptosis Inactivation ofcancer suppressor genes • Expression of altered geneproducts Loss of regulatory geneproduct • Clonal expansion • Additional mutations • Heterogeneity • MALIGNANTNEOPLASM
10.TREATMENT OPTIONS OF CANCER 1. Surgery: before 1955 2.Radiotherapy: 1955~1965 Chemotherapy: after1965 Immunotherapy Genetherapy
11. DIAGNOSIS OFCANCER • Biopsy- involves histological examination by a pathologist of a piece of tissue. • Imaging techniques– • CTscan, • MRI, • UTZ • Laboratorytest • Tumor markers(produced bycancer) • Example: • CA15-3- Breastcancer. • CA19-9 - Gastrointestinaltumours. • CA-125 - Ovariancancers. • PSA - Prostatecancers. 14 14
15. COMPARISON OF MYELOSUPPRESSIVE POTENTIAL OF CHEMOTHERAPEUTIC DRUGS
16.1 MECHANISM OF ACTION OFMETHOTREXATE Methotrexatepotently inhibits Dihydrofolate reductase(DHFR). This leads to decreased production of compounds adenine, guanine and thymidine and the aminoacids methionine and serine, depletion ofthymidine. Finally depressed DNA, RNA, and protein synthesis and, ultimately, to celldeath. FH2= dihydrofolate; FH4 = tetrahydrofolate; dTMP =deoxythymidine monophosphate; dUMP = deoxyuridine monophosphate.
16.2 MECHANISM OF ACTION OF6-MERCAPTOPURINE 6-Mercaptopurine penetrates target cells and be converted to the nucleotideanalog. This leads to inhibit the first step of denovo purine-ring biosynthesis This results innon- functional RNA and DNA.
16.3 MECHANISM OF ACTION OF5-FLUOROURACIL 5-Fluorouracil competes with deoxyuridine monophosphate for thymidylate synthase and reduce the thymidine. DNA synthesis decreases due to lack of thymidine, leading to imbalanced cellgrowth. 5-FU = 5-fluorouracil; 5-FUR = 5-fluorouridine; 5-FUMP = 5-fluorouridine monophosphate; 5-FUDP = 5-fluorouridine diphosphate; 5-FUTP =5-fluorouridine triphosphate; dUMP = deoxyuridine monophosphate; dTMP =deoxythymidine monophosphate. 5-FdUMP = 5-fluorodeoxyuridinemonophosphate. Dr.K.Saminathan.M.Pharm, M.B.A,Ph.D
16.4 MECHANISM OF ACTION OFGEMCITABINE Gemcitabine inhibits DNA synthesis by being incorporated into sites in the growing strand that ordinarily would contain cytosine. Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for the generation of deoxynucleoside triphosphates requiredfor DNA synthesis.
16.5 MECHANISM OF ACTION OF DOXORUBICIN ANDDAUNORUBICIN Doxorubicin and daunorubicin bind to the sugar- phosphate backbone of DNA. This causes localuncoiling. Which leadsto blocks DNA& RNA synthesis and catalyzed breakage supercoiled DNA strands, causing irreparable breaks. Catalyzes the reduction offree radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single- strand scission ofDNA.
16.6 MECHANISM OF ACTION OFBLEOMYCIN ADNA-bleomycin-Fe2+ complex appears to undergo oxidation to bleomycin-Fe3+. The liberated electrons react with oxygen to form superoxide or hydroxyl radicals, which in turn attack the phosphodiester bonds of DNA, resulting in strand breakage and chromosomalaberrations.
16.7 MECHANISM OF ACTION OFMECHLORETHAMINE Mechlorethamine is alkylates the N7 nitrogen of a guanine residue in one or both strands of a DNA molecule This alkylation leads to cross-linkages between guanine residues in the DNA chains and/or depurination, thus facilitating DNA strand breakage. Alkylation can alsocause miscoding mutations. Dr.K.Saminathan.M.Pharm, M.B.A,Ph.D
16. 11 MECHANISM OF ACTION OF ESTROGENS INPROSTATIC Flutamide,nilutamide and bicalutamide are synthetic, nonsteroidal antiandrogens used in the treatment of prostatecancer. Estrogens, such as ethinyl estradiol or diethylstilbestrol, had been used in the treatment of prostaticcancer. However, they have been largely replaced by the GnRH analogs because of fewer adverseeffects. Estrogens inhibit the growth of prostatic tissue by blocking the production of LH, thereby decreasing the synthesis of androgens in the testis. CANCER
16. 12 MECHANISM OF ACTION OFTAMOXIFEN Tamoxifen binds to the estrogen receptor and the complex fails to induce estrogen- responsive genes, and RNA synthesis does notensue. The result is depletion(down- regulation) of estrogen receptors, and the growth- promoting effects of the natural hormone and other growth factors aresuppressed. The action of tamoxifen is not related to any specific phase of the cellcycle.
16.13 MECHANISM OF ACTION OF IRINOTECAN&TOPOTECAN Normal unwindingof doublehelix Irinotecan and topotecan areinhibit the unwinding of doublehelix Con…
16.13 MECHANISM OF ACTION OF IRINOTECAN&TOPOTECAN Irinotecan and topotecan are semisynthetic derivatives.These drugs are S-phase specific. They inhibit topoisomerase I, which is essential for the replication of DNA in humancells.
16. 14 MECHANISM OF ACTION OF ETOPOSIDE&TENIPOSIDE Normal catalytic cycle of topoisonerase which is inhibited by the Etoposide and its analog,teniposide Con…
16. 14 MECHANISM OF ACTION OF ETOPOSIDE&TENIPOSIDE Etoposide and its analog, teniposide are semisynthetic derivatives of the plant alkaloid, They block cells in the late S to G2 phase ofthe cellcycle. Their major target is topoisomerase II. Binding of the drugs to the enzyme-DNA complex results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double-strand breaks
17.TOXIC EFFECTS OF ANTI CANCERDRUGS • Bone marrow toxicity (myelosuppression) with decreased leucocyte production and thus decreased resistance toinfection • Impaired wound healing • Loss of hair(alopecia) • Damage to gastrointestinalepithelium • Depression of growth inchildren • Sterility • Teratogenicity. Dr.K.Saminathan.M.Pharm, M.B.A,Ph.D
Acutetoxicity • Vomiting • Allergicreactions • Arrhythmias • Delayedeffects • Mucositis • Alopecia • Bone marrowsuppression • Chronictoxicities • Heart • Kidney • Liver • Lungs
18.CONCLUSION Every year, more than 1 million Americans and more than 10 million people worldwide are expected to be diagnosed with cancer, a disease commonly believed to bepreventable. Only 5–10% of all cancer cases can be attributed to genetic defects, whereas the remaining 90–95% have their roots in the environment and lifestyle. The evidence indicates that of all cancer-related deaths, almost 25– 30% are due to tobacco, as many as 30–35% are linked to diet, about 15–20% are due to infections, and the remaining percentage are due to other factors like radiation, stress, physical activity, environmental pollutantsetc. Therefore, cancer prevention requires smoking cessation, increased ingestion of fruits and vegetables, moderate use of alcohol, caloric restriction, exercise, avoidance of direct exposure to sunlight, minimal meat consumption, use of whole grains, use of vaccinations, and regular check-ups.
