Biomedical Engineering Reference
In-Depth Information
the.FDA.for.the.treatment.of.metastatic.breast.cancer.(MBC),.either.in.the.irst-line.setting.
in.combination.with.paclitaxel,.or.as.a.monotherapy.for.patients.who.had.received.at.least.
one.prior.chemotherapy.regimen. 57
8.3.2.4   Mechanism of Action of Trastuzumab
Trastuzumab. consists. of. two. antigen-speciic. sites. binding. to. the. HER2. receptor,. which.
prevent.the.activation.of.its.intracellular.tyrosine.kinase..The.mechanism.of.action.of.tras-
tuzumab.has.not.been.fully.characterized.and.appears.to.be.complex..Trastuzumab.exerts.
its.antitumor.therapeutic.effects.against.tumor.cells.with.HER2.overexpressed.by.several.
possible.mechanisms.
Herceptin.reduces.signaling.from.pathways.that.are.activated.by.HER2,.and.thus.pro-
motes.cell.cycle.arrest.and.apoptosis..These.pathways.include.the.PI3.kinase.(PI3K).and.
MAP.kinase.(MAPK).cascades..Research.shows.that.HER2.remains.at.the.same.level.after.
trastuzumab-based.treatment;.therefore,.it.is.still.unclear.whether.trastuzumab.downreg-
ulates.HER2. 58 .Trastuzumab.therapy.also.increases.membrane.localization.and.activity.of.
PTEN..Nagata.et.al..demonstrated.that.the.interaction.between.HER2.and.the.Src.tyrosine.
kinase.is.disrupted.in.response.to.trastuzumab.treatment,.leading.to.inactivation.of.Src.
with.subsequent.activation.of.the.PI3K.inhibitor.phosphatase.and.tensin.homolog.(PTEN).
the.protein.product.of.the.phosphatase.and.tensin.homolog.deleted.on.the.chromosome.
10.gene. 59 .Thus,.Herceptin.activates.the.PTEN.phosphatase,.resulting.in.rapid.Akt.dephos-
phorylation,.and.inhibits.cell.proliferation.
Trastuzumab.possesses.not.only.targeting.ability.but.also.therapeutic.effect,.compared.
to.many.targeted.agents..The.cytotoxic.property.enables.trastuzumab.to.block.prolifera-
tion. and. promote. cell. death,. which. may. be. related. in. part. to. induction. of. an. immune.
response.. Trastuzumab. activated. an. antibody-dependent. cellular. cytotoxicity. (ADCC).
response.in.multiple.breast.cancer.cell.lines. 60,61 .Natural.killer.(NK).cells,.expressing.the.Fc.
gamma.receptor,.are.a.principal.immune.cell.type.involved.in.ADCC..NK-mediated.cell.
lysis.is.activated.after.trastuzumab.binds.to.the.Fc.gamma.receptor..Trastuzumab.recruits.
immune. effective. cells. that. are. responsible. for. antibody-dependent. cytotoxicity,. which.
has.been.put.forward.in.preclinical.models..Results.showed.that.mice.bearing.BT474.HER-
2-overexpressing. xenografts. demonstrated. a. tumor. regression. rate. of. 96%. when. treated.
with.Herceptin. 62 .However,.mice.lacking.the.Fc.receptor.lost.much.of.the.protective.effect.
of.Herceptin,.with.only.29%.tumor.growth.inhibition.observed..Therefore,.NK.cells.and.
ADCC.are.important.contributors.to.the.cytotoxic.activity.of.Herceptin..However,.it.should.
be.noted.that.patients.with.advanced.metastatic.breast.cancer.are.immunosuppressed.and.
may.not.be.the.optimal.population.to.study..Additional.studies.are.needed.to.better.under-
stand.the.importance.of.ADCC.in.mediating.the.response.to.Herceptin.
Overexpression. of. HER2. in. human. cancer. cells. is. associated. with. increased. angio-
genesis. 63 .Trastuzumab.might.also.play.a.role.as.an.antiangiogenic.agent,.as.it.has.been.
shown.to.induce.normalization.and.regression.of.the.vasculature.in.a.human.breast.tumor.
model. which. is. HER2. positive. 64 . Trastuzumab. suppresses. angiogenesis. by. both. induc-
tion.of.antiangiogenic.factors.and.repression.of.proangiogenic.factors..Expression.of.mul-
tiple.proangiogenic.factors.was.reduced,.while.expression.of.antiangiogenic.factors.was.
increased.in.tumors.with.therapy.of.trastuzumab,.compared.with.control-treated.tumors.
in. vivo. 65 . Moreover,. the. combined. use. of. trastuzumab. and. paclitaxel. more. effectively.
inhibited. HER2-mediated. angiogenesis.than.either. treatment.alone,. which.relects.more.
pronounced.antitumor.effects. 64 .Trastuzumab.may.also.prevent.ligation.of.HER2.with.its.
ligand,.by.which.apoptosis.may.be.induced. 66
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