Fluorouracil

5-Fluorouracil acts as a "false" pyrimidine inhibiting the formation of the DNA base thymidine.23,44 The main mechanism by which it accomplishes this is by inhibiting the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. 5-Fluorouracil must first be metabolized to its active metabolite (F-dUMP). Additionally, metabolites of 5-fluorouracil may incorporate into RNA inhibiting its synthesis.

5-Fluorouracil is commonly used in the adjuvant and metastatic treatment of colon and rectal cancers. Various dosing administration techniques and schedules have been developed with 5-fluorouracil including IV bolus every 3 to 4 weeks, IV continuous infusion, weekly IV boluses and IV boluses, followed by continuous infusions of 5-fluorouracil. Clinical studies comparing efficacy of bolus and continuous infusion schedules generally favor continuous infusion of 5-fluorouracil. This is consistent with evidence that suggests that the duration of infusion may be an important determinant of the biologic activity of 5-fluorouracil, particularly because of its short plasma

23 33 44

half-life, S-phase specificity, and relatively slow growth of colon tumors. ' '

Clinical significant differences in toxicity also differ based on the dose, route, and schedule of 5-fluorouracil administration. Leukopenia and mucositis are the primary dose-limiting toxicities of bolus 5-fluorouracil, whereas palmar-plantar erythrodyses-thesia ("hand-foot syndrome'3) and diarrhea occur most frequently with continuous infusions of 5-fluorouracil.23, 3,34 Health care practitioners can offer valuable patient advice to decrease the impact of these adverse effects. Patients can be informed to suck on ice chips prior to and for up to 30 minutes after 5-fluorouracil boluses to decrease the incidence of mucositis. Hand-foot syndrome, characterized by painful swelling and redness of the soles of the feet and palms of the hand, can be minimized with loose fitting clothing and keeping skin moist. Additional toxicities include moderate nausea and vomiting, skin discoloration, nail changes, photosensitivity, and neurologic toxicity.

Table 91-7 FDA-Approved Drugs Used in Colon Cancer

M«h aaism of Action

Common Tonicities

Doiinfl Adjustment! foi Renal ur Hl'pj! it Dy ifu nt r ic.rt Or Pharmacol nelicConsiderationî

5-F l^srouiMil taperltafome (XvVxia}

irinoKtan (t'ampicftar}

CMlIfmSrt

0evaciajmal> (Avatflnil

ÜJlUiiniab

(Eitttw)

P<imtumumab (VL-ilW

hMtaton'ofihe enzyme

Ihymldylate synlhase, the i JtHimiliny SKp in lhyink:iJK> fcfoiat-on

Myek)Eiippr«it3nin(l mucosals with holus

4k*iiiriis[ij[iori Oisrrhfti ^vd harid-fcí* syndrome wilt* continuous infusion Kmiiilieï

Skin discotoiahoa nail (tanges, photosenijtivlty,

.Vul liSak ;ly

Oaly active piodrngof Similar to conimnous infusion s-fh/vnjiarll

> I IlkjkkjwJI. orco ac I ri'jiixH. ¡he nwíhflllhm option is (he ume

Totfli»iiKraie inhifcirct îhst foi™ a cgmptex wiih iOwkfUty bound LW lopoisonietasii1 enzyme and Interferes wllh the CNA pote«

Sin Jai tû othci platinum in (M ¡t binii to the U-7 position ■si guanioft which iwJb in croivlii^ing of (JNA jnd doubt' itundod ONA breaks wionotkviai antiix*fy thaï binds toVïGF and iriwWts jngioyiftiii

Hrïdi (o lhettl surface EGFR; preveniin*) ECÍ and Tcjf-(f birKÍnig. TFiis decreased toll (Holiñffiiionofíiivíf cells

ürndaf to cetuïimab

D&t-RfWt/np Fatly and late diarrhea AtWütuMf fewiívi; HftHropenia nausea and Imming

CK> nst i \( t> rijöiil rlrwter lhan 5 int^idl. (flipmol/L)

OG 30-50 rmH/mln dewsw Harting dose lt> JS^t Of 1 he oiiyinal dose tK> not give if Mtei Than í&mUimn l>o«se dose one se^ei in Clients Wfitna honrniygcuft UGTlAl'iä olk-k'. Tills dCirtas« IlttlMpHit rfer.ihfjli'jn cliiinoiecanand increases lhe lowidty

DOw^rufin^

Actin* (wi:hin first 2 dayiO dr*J |)ei Astern (cheater Ihiin M days! neuropathies

AddHSMftMHtK

Aiwihylaaii-llke "eat tions, flyipnea, nausea, vomiting

CKHt-Himnf

Hypertension, Heeding-fptscxles, thronnlhotk: M(HS

¿Aftiioiw I KKWHfS;

flaie perioralion oi Hie bowel picfinurea

Dose-limiting:

InfiisUn-rclîni'd (mettons, arwiform ilum rasJi

MtliHonal SWUfi®

liuiinta hypoiiviyn«efiika. hypocalcemia. Interstitial Ii>iyj disease

Dose-limiting:

Arrii.'iiviiii

Mditionaltoiticinei:

infusfcin-ieUKd i«c tkxis. diarrhea hypermagnesemia, hypocalcemia, interstitial lung disease*

Mo famnaldiMÉ adiuslnienl though ííHinjft in pítiecift tvinh mild Id moderate renal dysfunction ivkjne

KfHÏ wild-typo only

WMÎ vuldlvpeonly

An additional determinate of 5-fluorouracil toxicity, regardless of the method of administration, is related to its catabolism and pharmacogenomic factors. Dihy-dropyrimidine dehydrogenase (DPD) is the main enzyme responsible for the catabolism of 5-fluorouracil to inactive metabolites.46 A number of polymorphisms in DPD have been identified, in which patients have a complete or near-complete deficiency of this enzyme. This results in unusually severe toxicity, including death, after the administration of 5-fluorouracil. Approximately 3% of patients have a complete lack of DPD activity with other patients demonstrating a partial deficiency in enzyme activity. Although patients may be tested for level of DPD activity, it is not routinely done, but may be considered in patients who develop severe toxicity after 5-fluorouracil administration.

Leucovorin is commonly given with 5-fluorouracil. Leucovorin acts to increase the affinity of 5-fluorouracil to thymidine synthase, thus increasing the pharmacologic

activity of 5-fluorouracil. Leucovorin is most effective when administered prior to 5-fluorouracil and can be given by IV bolus or as a continuous infusion. Health care practitioners can also expect an increase in 5-fluorouracil toxicities (leukopenia, mucositis, and diarrhea) when leucovorin is given in combination with 5-fluorouracil.

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