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Irinotecan
Irinotecan is used for the treatment of colorectal, lung, and ovarian cancer. Irinotecan
inhibitstopoisomeraseIandfunctionscell-cyclephasespecific.Itisconvertedtotheactive
metaboliteSN-38.Themajorrouteofeliminationisthroughthebile.Theactiveformofthe
drug is metabolized by the polymorphic enzyme UGT1A1*28. Approximately 10% of the
NorthAmerican population ishomozygousfor this polymorphism andis at greater riskof
experiencingneutropenia.Thedose-limitingtoxicities arediarrhea,especiallyinpatients
65yearsofageandolder,andmyelosuppression.Commonsideeffectsincludeneutropenia,
vomiting,andmildalopecia(114).
Topotecan
Topotecanisusedforthetreatmentofplatinum-resistantovariancancer,cervicalcancer,and
smallcelllungcancer.ItisaderivativeofcamptothecinandinhibitstopoisomeraseIactivity
(88).Itsfunctioniscell-cyclephasespecific.About60%ofthedrugisexcretedintheurine.
Themaindose-limitingtoxicityismyelosuppression.Commonsideeffectsincludenausea
andvomiting,diarrhea,alopecia,arthralgia,andmyalgia(115).
MitomycinC
Mitomycin C is another antibiotic that was isolated from the Streptomyces fungus. It is
activated in vivo into an alkylating agent that can bind DNA, producing crosslinks and
inhibiting DNA synthesis. It has a quinone moiety that can generate free radical reactions
similartothoseseenwiththeanthracyclineantibiotics.Itisadministeredintravenouslyandis
degradedprimarily bymetabolism. Renalclearance isnot amajormechanism ofexcretion
(116).
Antimetabolites
The antimetabolites interact with vital intracellular enzymes, leading to their
inactivation, or to the production of fraudulent products incapable of normal intracellular
function. Their structures resemble analogs of normal purines and pyrimidines, or they
resemble normal substances that are vital for cellular function. Some antimetabolites are
activeasintactdrugs,andothersrequirebiotransformationtoactiveagents.
Mechanism
Althoughmanyoftheseagentsactatdifferentsitesinbiosyntheticpathways,theyappearto
exerttheirantitumoractivitybydisruptingfunctionscrucialtotheviabilityofthecell.These
effectsareusuallymoredisruptivetoactivelyproliferatingcells;thus,theantimetabolitesare
classedingeneralascellcycle–specificagents.
Although hundreds of antimetabolites have been investigated, only a few are commonly
used.Theyincludethefollowing:
1. Thefolateantagonistmethotrexate,whichinhibitstheenzymedihydrofolatereductase
2. Thepurineantagonists6-mercaptopurineand6-thioguanine
3. Thepyrimidineantagonists5-fluorouracil(5-FU)andcytarabine
4. Thenucleosideanaloggemcitabine
Inmostinstances, the antimetabolites are used in combinations becauseoftheircell cycle
specificityandtheircapacityforcomplementaryinhibition.Antimetabolitescommonlyused
inthetreatmentofgynecologicmalignanciesaresummarizedinTable4.11.
Table4.11Antimetabolites
Drug
Routeof
Administration CommonToxicities DiseasesTreated
5-fluorouracil IV Myelosuppression,
nauseaandvomiting,
anorexia,alopecia
Breast,cervicalcancer
Capecitabine PO Diarrhea,hand–foot
syndrome
Breast,coloncancer
Methotrexate PO,IV,IT Mucosalulceration,
myelosuppression,
allergicpneumonitis;
withintrathecal:
meningealirritation
Choriocarcinoma,breast
cancer
Gemcitabine IV Myelosuppression Ovarian,breastcancer,
leiomyosarcoma
Pemetrexed IV Myelosuppression Mesothelioma,non-small
celllungandovarian
cancer
IV,intravenous;PO,oral;IT,intrathecal.
Drugs
Cytarabine
Cytarabine is used for the treatment of leukemia, lymphoma, and leptomeningeal
carcinomatosis.Itrequiresintracellularactivationtoitsphosphorylatedderivative.Thelatter
inhibits DNApolymerase that is involved in the conversion of cytosine to deoxycytidine.
Commondose-limiting toxicityismyelosuppression. Other common side effects include
nausea,vomiting,mucositis,diarrheaandneurotoxicity(117).
5-Fluorouracil
5-Fluorouracil is used for the treatment of gastrointestinal malignancies, as well as
breast, pancreatic, and head and neck cancer. It requires activation to cytotoxic
metabolites.It interferes with DNA synthesis by blocking thymidylatesynthetase (TS), an
enzymeinvolvedintheconversionofdeoxyuridylicacidtothymidylicacid.Metabolitesare
incorporatedintoseveralRNAspecieswhichinterferewithproteinsynthesis.Incorporation
of another metabolite into DNA results in inhibition of DNA synthesis and function. 5-
fluorouracil is cell-cycle S-phase specific but acts in other cell cycle phases as well. 5fluorouracil rapidly enters spinal fluid and malignant effusions. Most of the degradation
occurs in the liver and inactive metabolites are excreted in the urine and bile. The main
dose-limitingtoxicityismyelosuppression,whilecommonsideeffectsincludemucositis
anddiarrhea.Othersideeffectsincludehand–footsyndromewithprotractedinfusiontimes;
alopeciaisrarelyobserved(118).
Capecitabine
Capecitabineisusedforthetreatmentofbreastandcoloncancer.Itisanoralmedicationand
it is a prodrug 5′-deoxy-5-fluorouridine, which is converted in vivo to 5-fluorouracil.
Degradation is similar to 5-fluorouracil; the dose limiting toxicity has been diarrhea and
hand–footsyndrome(119).
Gemcitabine
Gemcitabine is used for the treatment of patients with pancreatic, bladder, lung, and
ovariancancer,aswell assoft tissuesarcomas.It is a fluorine-substituteddeoxycytidine
analog.Itfunctionsasacellphasespecificagent,primarilykillingcellsinS-phase.However,
gemcitabinealsoblockstheprogressionofcellsthroughtheG1toSphase.Gemcitabine is
metabolizedintracellularlyandincorporatedintoDNA.Themaindose-limitingtoxicityis
myelosuppression.Commonsideeffectsincludenausea,vomiting,diarrhea,stomatitis,
flu-likesymptoms,andskinrash.Alopeciahasbeenonlyrarelydescribed(120).
Methotrexate
Methotrexateisusedforawidevarietyofconditionsincludingthetreatmentofbreast
cancer and gestational trophoblastic disease. Methotrexate blocks the enzyme
dihydrofolatereductase,preventingformationofreduced(tetrahydro-)folicacid.Tetrahydro
folic acid is crucial to the transfer of carbon units in a variety of biochemical reactions.
Methotrexate thus blocks formation of thymidylate from deoxyuridylate and prevents
synthesis of DNA. Leucovorin can reverse the immediate cytotoxic effects of
methotrexate.Generally,1mgofleucovorinisgivenforeach1mgofmethotrexate.Dose-
limiting toxicity for high-dose regimens include nausea and vomiting. Methotrexate
neurotoxicity depends on the dose and route of administration; following intrathecal
administration, methotrexate can produce an acute aseptic meningitis that is usually selflimited(121).
Pemetrexed
Pemetrexedisusedforthetreatmentofmesothelioma,non–small-celllungandovarian
cancer. It is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell
cycle.Inhibitionofthefolate-dependentenzymethymidylatesynthetase(TS)isthemainsite
of action. It also inhibits dihydrofolate reductase and two formyltransferases. The drug is
mainlyclearedby the kidneys. About 90% of the drug is excretedunchangedinthe urine
within24hours.Patientswithinsufficientfolateintakemaybeatincreasedriskoftoxicity.A
baselinehomocysteinelevel >10is predictiveforthedevelopmentof grade3to4toxicity.
Dose-limitingtoxicityis myelosuppression. All patients are given 1 mg of folic acid by
mouthandsubcutaneousvitaminB12injectionsevery3weeksduringpemetrexedtreatment
to reduce drug toxicity.Steroid medications the day before, the day of, and the day after
pemetrexedtreatmentreducedrugtoxicities(122).
PlantAlkaloids(MitoticSpindleAgents)
The most commonly used plant alkaloids are the vinca alkaloids, natural products derived
fromthe commonperiwinkleplant (Vincarosea)(Table4.12).Like mostnaturalproducts,
thesecompoundsarelargeandcomplexmolecules,butvincristineandvinblastinedifferonly
by a single methyl group on one side chain. Paclitaxel,docetaxel, and ixabepilone inhibit
microtubuleassemblyduringtheMphaseofthecellcycle.
Mechanism
Themitoticspindleisformedbytheassemblyof microtubulesthat arecomposed ofalpha
andbetatubulin.Vincaalkaloidsbindtothetubulindimer,whichisinhibitingassemblyof
microtubulesduringtheMphaseofthecellcycle.Athighconcentrations,thesedrugshave
effectsonnucleicacidandproteinsynthesis.Thetaxanesbindtomicrotubulesandpromote
their assembly. They also promote resistance to depolymerization, which leads to the
productionofnonfunctionalmicrotubules.
Drugs
Paclitaxel
Paclitaxel is used for the treatment of many cancers including breast, ovarian, lung,
cervical,andpancreatic.It was originally isolated from the bark of the pacific yew tree
taxus brevifolia. Since the mid-1990s, paclitaxel has been chemically synthesized. Unlike
othertubulintargetingdrugssuchascolchicinethatinhibitsmicrotubuleassembly,paclitaxel
stabilizes the microtubule polymers and protects them from disassembly. As a result,
chromosomes are unable to achieve a metaphase spindle configuration. This blocks the
progressionofmitosisandprolongedactivationofthemitoticcheckpointtriggersapoptosis.
ThedrugisextensivelymetabolizedinthehepaticP450microsomalsystem.Morethan75%
of the drug is excreted in the feces. Dose-limiting toxicity is neutropenia (123).
Carboplatin, cisplatin, and cyclophosphamide decrease paclitaxel clearance and thus
increasemyelosuppression.Theyshouldbeadministeredafterpaclitaxel.
Table4.12PlantAlkaloids(MitoticSpindleAgents)
Drug
Routeof
Administration CommonToxicities DiseasesTreated
Vincristine IV Neurotoxicity,
myelosuppression,
cranialnervepalsies,
gastrointestinal
Ovariangermcell,
sarcomas,cervical
cancer
Vinblastine IV Myelosuppression,
alopecia,nauseaand
vomiting,neurotoxicity
Ovariangermcell
Paclitaxel IV Myelosuppression,
alopecia,allergic
reactions,neuropathy
Ovarian,breastcancer
Vinorelbine IV Myelosuppression,
constipation,peripheral
neuropathy
Ovarian,breastcancer
Docetaxel IV Myelosuppression,
alopecia,hypersensitivity
reactions,peripheral
edema
Breast,ovariancancer
Nab-paclitaxel IV Myelosuppression,
alopecia,peripheral
neuropathy
Breast.Pancreatic,nonsmallcelllung
Eribulin IV Myelosuppression,
peripheralneuropathy
Breastcancer,
liposarcoma
Ixabepilone IV Myelosuppression,
mucositis,peripheral
neuropathy
Breast,endometrial
cancer
IV,intravenous.
A common side effect is hypersensitivity, which is manifested by cutaneous flushing,
hypotension, bronchospasm, urticaria, diaphoresis, pain, or angioedema. Reactions usually
develop within 10 minutes of starting the treatment. Premedication with corticosteroids,
diphenhydramine, and famotidine has been advised. Reactions may be caused by the
solvent cremophor or by the drug itself. Another common side effect is peripheral
neuropathy, particularly with higher dosage schedules. The distribution of neuropathy is
typically stocking- and glove-like and consists of paresthesia and loss of proprioception,
whichmaytakemonthstoresolve.Alopeciaoccursin90%ofpatients,isusuallytotal,and
is apparent within 4 weeks of treatment. Other side effects include nausea, vomiting,
mucositis,ordiarrhea.
Protein-boundPaclitaxel(Nab-Paclitaxel)
Nab-paclitaxelisasolvent-freeformulationofpaclitaxel,whichisusedforthetreatment
ofbreast,pancreatic,and non–small-cell lung cancer. The paclitaxel is albumin-bound,
which helps make the drug more water-soluble and facilitates the transport across cell
membranes. Since solvent-related hypersensitivity reactions do not occur with nap-
paclitaxel,thosemedications commonly used for paclitaxel are not necessary. Other doselimitingtoxicitiesandcommonsideeffectsareverysimilartopaclitaxel(124).
Docetaxel
Docetaxelisusedforthetreatmentofmanycancersincludingbreast,ovarian,stomach,
esophagus, head and neck, and prostate. The drug is prepared semi-synthetically,
beginning with a precursor extracted from the needles of the European yew tree. It is an
inhibitor of microtubular depolymerization and is extensively metabolized in the hepatic
P450microsomalsystem.Themaindoselimitingtoxicityismyelosuppression.Otherside
effects include alopecia, maculopapular rash, discoloration of fingernails, mucositis,
fatigue, and occasionally hypersensitivity. The neurotoxicity is slightly less when
comparedtopaclitaxel.Premedicationshould include4-mg dexamethasone twicedaily the
daybeforeandafterchemotherapy,toreducefluidretention,skinrash,andallergicreactions
(125).
Eribulin
Eribulinisanon-taxanemicrotubuleinhibitor,thatisahalichondrinBanalog.Itinhibitsthe
formationofmitoticspindles,causingarrestofthecellcycleattheG2/Mphase.Eribulin
suppressespolymerizationofmicrotubuleswithoutaffectingdepolarization.Morethan80%
of the drug is excreted unchanged in the feces. The main dose-limiting toxicities are
myelosuppressionandperipheralneuropathy(126).
Ixabepilone
Ixabepilone is used for the treatment of refractory locally advanced or metastatic breast
cancer. This drug is an epothilone B analog. It binds to the beta tubulin subunit of the
microtubule,thusarrestingthecellcycleattheG2/Mphaseandinducingapoptosis.Likethe
other mitotic spindle inhibitors, it is excreted mostly in the feces, with minimal renal
excretion.Thedoselimitingtoxicitiesaremyelosuppressionandcentrifugalneuropathy.
Alopeciaiscommon andoccasional sideeffectsarehand–footsyndromeand skinand nail
disorders(127).
Vinblastine
Vinblastineisusedforthetreatmentoflymphomasandtesticularcarcinoma.Thedrugis
a plant alkaloid which binds to microtubular proteins. It also inhibits RNA synthesis by
affectingDNA-dependentRNApolymerase.VinblastinecausesarrestoftumorcellsintheM
phaseofthecellcycle.Thedrugismetabolizedthroughtheliverandpredominantlyexcreted
in the bile. The major dose-limiting toxicity is neutropenia, while other side effects
includenausea,vomiting,diarrhea,mucositis,andinterstitialpneumonitis(128).
Vincristine
Vincristineisusedinawidevarietyofmalignanciesincludinggestationaltrophoblastic
tumors.Thepharmacologicmechanismsofmetabolismarethesameasforvinblastine.The
dose-limiting toxicity is peripheral neuropathy, which develops universally. Alopecia
occursin20–50%ofpatients,whileraresideeffectsincludenauseaandvomiting(128).
Vinorelbine
Vinorelbineisusedforthetreatmentofnon–small-celllung,breast,andovariancancers
as well as lymphoma. It is a semisynthetic alkaloid derived from vinblastine. It inhibits
tubularpolymerization,disruptingtheformationoftubulesduringmitosis.Mostofthedrug
is metabolized in the liver and excreted in the bile. Dose-limiting toxicity is
myelosuppression.Other sideeffectsinclude neuropathy, nausea, vomiting,and stomatitis
(129).
Acknowledgments
TheauthorswouldliketoacknowledgeDr.MaurieMarkman,whosignificantlycontributed
toearlierversionsofthischapter.
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