Historical Perspective: Targeted cancer therapies

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University of Toronto St. George
Pharmaceutical Chemistry

Cells in multicellular organisms continuously signal each other and the environment This leads to proliferation differentiation and apoptosis In cancer there is a loss of balance in signalingProblem Humans go through a large number of cell divisions in lifespan each divisionpossible mutation Our bodies evolve defense against cancer formationOne normal cell typemultiply uncontrollablychaos tumorTraditional Cancer ChemotherapythMajor medical advance of 20 centuryIn certain cancers chemotherapy is curativeAdjuvant chemotherapy chemotherapy along with removal of tumor for breast colon and lung cancer increases survival benefit Narrow Therapeutic IndexSide effects Alopecia GI symptoms Myelosuppression Decrease in immune cellsResponses are partial unpredictableMore options are neededCancer mortality from 4 major killers has decrease in the pastcenturyMale Stomach Female Stomach Colorectal Uterine cancer has decreasedReasons Improvements in food storage practices decreased HPylori infection rates improved screening early detectionMost cancers are resistant to traditional chemotherapy Mortality has not significantly changes Lung cancer has increasedResearch findings are only starting to be exploited in clinicTherapy chosen based on diagnostic categories Particular tumor type Stage of disease all receives same treatmentBiological heterogeneity of tumors significant with respect to drug responsiveness just starting to be understoodLimited available drugslimited possibility to exploit differences for treatmentConventional cytotoxic drugs interact with DNA microtubulesprevent cell replication but NOT specific to cancer cellsTargeted therapies Drug targets molecular pathwayLimited possibilities only a subset of defective proteins in cancer cells are attractive targets for drug developmentDrugs should be low molecular weight organic compounds that inhibit rather than activate biochemical functions of proteinsTumor suppressorscancer development via their absence or mutation Needs a drug to reactivate them
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