Cancer Cancer is a disease in which the cellsdivide and grow uncontrollably and rapidlyforming tumors. Cancer is thought to be caused by tobaccouse, certain infections, radiation, lack ofphysical activity, obesity and by theinteraction between genetic susceptibilityand environmental toxins. There are over 200 different known cancersthat afflict humans
Chemotherapy Chemotherapy is the treatment of cancerwith one or more cytotoxic antineoplasticdrugs . Traditional chemotherapeutic agentsact by killing cells that divide rapidly, one ofthe main properties of most cancer cells.This means that chemotherapy also harmscells that divide rapidly under normalcircumstances.
Targeted therapy This results in the most common side-effects of chemotherapy: myelosuppression(decreased production of blood cells),mucositis (inflammation of the lining of thedigestive tract) and alopecia (hair loss). Some newer anticancer drugs (monoclonalantibodies) are not indiscriminatelycytotoxic, but rather target proteins that areabnormally expressed in cancer cells andthat are essential for their growth. Suchtreatments are often referred to as targetedtherapy
Types of anticancer drugs According to the source of drugs,the majorityof chemotherapeutic drugs can be divided into Alkylating agents, Antimetabolites, Antibiotics, Plant alkaloids, Topoisomerase inhibitors and Other antitumour agents. Some newer agents do not directly interferewith DNA. These include monoclonalantibodies and the new tyrosine kinaseinhibitors
Mechanism of anticancerdrugs Block nucleic acid (DNA, RNA)biosynthesis Directly destroy DNA and inhibit DNAreproduction Interfere transcription and block RNAsynthesis Interfere protein synthesis and function Influence hormone homeostasis
Alkylating agents Alkylating agent used in cancer treatmentattaches an alkyl group to DNA. It forms acovalent bond with the nucleophilicsubstanceThe nitrogen at position 7(N7) ofguanidine residues in DNA is stronglynucleophilic and is especially susceptible.Othermolecular sites such as N1 and N3 of adenineand N3 of cytosine may also be effected.It leadto Cross linking of bases Abnormal base pairing & DNA strand breakage
Antimetabolites Antimetabolites are structurallyrelated to normal componente of DNA.They prevent these substances frombecoming incorporated in to DNAduring the "S" phase of the cell cycleby competing with the purines andpyrimidines in DNA or RNA synthesiswhich in turn stops the normaldevelopment and division.
Methotrexate(Abitrexate®) Methotrexate is the most widely usedantimetabolite in cancerchemotherapy. It mainly acts byinhibiting the enzyme dihydro folatereductase(DHFR),which is essential inthe conversion of folate to THF andlack of the co enzyme THF leads toinhibition of DNA synthesis
6-Mercaptopurine(Purinethol®) 6-Mercaptopurine is an analogue of purineinhibits purine nucleotide synthesis andmetabolism and is highly effectiveanticancer drug. It is a purine analogue of the nucleobaseguanine. It incorporates into DNA during thesynthesis phase (S-phase) of the cellresulting in the DNA synthesis inhibitionTioguanine
5-Fluorouracil(Adrucil®) 5-Fluorouracil is an analogue ofuracil(pyrimidine) that lead to the inhibition ofDNA. It acts as a thymidylate synthaseinhibitor. Interrupting the action of thisenzyme blocks synthesis of the pyrimidinethymidine, which is a nucleoside required forDNA replication
Hydroxyurea(Hydrea®)It is an antineoplastic drug thatreduces the production ofdeoxyribonucleotides through theinhibition of the enzymeribonucleotide reductase thatcatalyzes the formation ofdeoxyribonucleotides fromribonucleotides
Plant alkaloids Mitotic spindles are very importantbecause they help to split the newlycopied DNA such that a copy goes toeach of the two new cells during celldivision. These drugs disrupt theformation of these spindles andtherefore interrupt cell divisionVincristine
Vinca alkaloids-Vinblastine (Velban®),Vincristine (Oncovin®) Binds to the microtubular protein tubulinin a dimeric form The drug-tubulin complex adds to theforming end of the microtubules toterminate assembly Depolymerization of the microtubulesoccurs Resulting in mitotic arrest at metaphase,dissolution of the mitotic spindle, andinterference with chromosomesegregation
Topoisomerase inhibitors Topoisomerases are essential enzymesthat maintain the topology of DNA.Inhibition of type I or type IItopoisomerases interferes with bothtranscription and replication of DNA byupsetting proper DNA supercoiling. Some type I topoisomerase inhibitorsinclude camptothecins: irinotecan andtopotecan. Examples of type II inhibitors includepodophyllotoxins,
AntibioticsActinomycin It is isolated from soil bacteria of the genusStreptomycescell biology, Actinomycin D isshown to have the ability to inhibittranscription. It does this by binding DNA atthe transcription initiation complex andpreventing elongation of RNA chain by RNApolymerase
Anthracyclines Anthracyclines are a class of drugs(CCNS or cell-cycle non-specific) usedin cancer chemotherapy derived fromStreptomyces bacterium. nhibits DNAand RNA synthesis by intercalatingbetween base pairs of the DNA/RNAstrand, thus preventing the replication ofrapidly-growing cancer cells. Inhibitstopoisomerase II enzyme, preventing therelaxing of supercoiled DNA and thusblocking DNA transcription and
Dactinomycin Binds to double stranded DNA throughintercalation between adjacent guanine-cytosine base pairs Inhibits all forms of DNA-dependent RNAsynthesis Binds to DNA through an antibiotic-Mg2+complex This interaction interrupts DNA-directed RNAsynthesisPlicamycin
Bleomycin It is a drug used in cancer chemotherapy. Itis an anthracycline antibiotic Doxorubicininteracts with DNA by intercalation andinhibition of macromolecularbiosynthesis.This inhibits the progression ofthe enzyme topoisomerase II, which relaxessupercoils in DNA for transcription Bleomycin acts by induction of DNA strandbreaksDoxorubicin(Adriamycin®)
Hormone therapyAromatase inhibitors Aromatase inhibitors are an importantclass of drugs used for the treatment ofbreast cancer At menopause, estrogen production inthe ovaries ceases, but other tissuescontinue to produce estrogen throughthe action of the enzyme aromatase.When the action of aromatase isblocked, estrogen levels in post-menopausal women can drop toextremely low levels, causing growtharrest and/or apoptosis of hormone-responsive cancer cells
MONOCLONAL ANTIBODIES Monoclonal antibodies such asRituximab and Trastuzsumab are alsoused in the cancer chemotherapy. This antibodies activate the hostimmune mechanism and kills thecancer cells.
RADIOACTIVE ISOTOPES Radioactive isotopes are used in thetreatment of certain tumours by theirproperty of producing ionization in thecells,thereby causing cell destruction. Eg.Radioactive Iodine is used inthyroid carcinoma
Some drugs areCell Cycle Nonspecific Agents (CCNSA)drugs that are active throughout the cell cycle Alkylating AgentsAntibioticsCell Cycle Specific Agents (CCSA)drugs that act during a specific phase of thecell cycleS Phase Specific Drug:Aantimetabolites, Topoisomerase InhibitorsM Phase Specific Drug:Vinca Alkaloids, TaxanesG2 Phase Specific Drug:Bbleomycin