CLINICAL PHARMACOLOGY OF SELECTED ANTINEOPLASTIC AGENTS IN THE
MANAGEMENT OF GESTATIONAL TROPHOBLASTIC DISEASES
Ma. Stephanie Fay S. Cagayan, M.D., FPOGS, FPSECP, FPSSTD Gestatina! t"ph#!asti$ nep!asia %GTN& has n' #e$(e ne ) the (st $*"a#!e ) h*(an (a!ignan$ies sin$e it 'as )i"st "ep"te+ as a "a"e +isease ) y*ng '(en that 'as *ni)"(!y )ata! *nti! the int"+*$tin ) (etht"e,ate #y Li an+ ass$iates in -./0. Gestatina! t"ph#!asti$ nep!as( #e!ngs t a g"*p ) (a!ignant t*("s 1e"y "espnsi1e t $he(the"apy. It is a +isease state that $(p"ises !'2 "is3 +iseases that $an #e $*"e+ 'ith si(p!e "e!ati1e!y nn2t,i$ t"eat(ent, t e,t"e(e!y agg"essi1e t*("s that "e4*i"e spe$ia!i5e+ (anage(ent. 6ith the int"+*$tin ) pha"(a$the"apy in the t"eat(ent ) gestatina! t"ph#!asti$ +iseases as +e(nst"ate+ #y He"t5 an+ $!!eag*es at the Natina! Can$e" Instit*te s(e /7 yea"s ag, the $*"e "ate )" these t*("s has stea+i!y in$"ease+ an+ n' e,$ee+s .78. Che(the"apy p!ays an i(p"tant "!e in the t"eat(ent ) these $an$e"s #e$a*se t"ph#!asti$ t*(" $e!!s a"e p"e1ente+ )"( (*!tip!ying, in1a+ing, (etastasi5ing an+ 3i!!ing the hst 'ith the *se ) antinep!asti$ +"*gs. Mst +"*gs in $*""ent *se a"e anti p"!i)e"ati1e in nat*"e an+ #e$a*se $e!! (*!tip!i$atin is a $ha"a$te"isti$ ) #th n"(a! $e!!s as 'e!! as $an$e" $e!!s, the ga! in se!e$ting an e))e$ti1e +"*g is t )in+ an agent 'hi$h has a (a"3e+ inhi#it"y e))e$t t the $an$e" $e!!s 'ith (ini(a! t,i$ e))e$t t the n"(a!!y p"!i)e"ating $e!!s. 9n'!e+ge ) $an$e" $e!! $y$!e an+ pp*!atin 3ineti$s is th*s essentia! in *n+e"stan+ing the pha"(a$!gi$ p"pe"ties ) anti$an$e" +"*gs. The past th"ee +e$a+es ha1e +e(nst"ate+ (a:" e))"ts #y #th g1e"n(ent an+ p"i1ate pha"(a$e*ti$a! )i"(s t +e1e!p n1e! +"*gs th"*gh #th e(pi"i$ s$"eening an+ "atina! +esign ) ne' $(p*n+s )" $an$e" t"eat(ent. These a+1an$es in$!*+e the synthesis ) pepti+es an+ p"teins 'ith "e$(#inant DNA te$hni4*es an+ (n$!na! anti#+ies. P"(ising agents that + nt ha1e e,$essi1e t,i$ity a"e then a+1an$e+ t phase I $!ini$a! t"ia!s, 'he"ein thei" pha"(a$!gi$ an+ t,i$ e))e$ts a"e *s*a!!y teste+ in patients 'ith a+1an$e+ $an$e". I+ea! anti$an$e" +"*gs '*!+ e"a+i$ate $an$e" $e!!s 'ith*t ha"(ing n"(a! tiss*es. ;n)"t*nate!y, n $*""ent!y a1ai!a#!e agents (eet this $"ite"in, an+ $!ini$a! *se ) these +"*gs in1!1es a 'eighing ) #ene)its against t,i$ity in a sea"$h )" a )a1"a#!e the"ape*ti$ in+e,. CONCEPTS IN T;MOR BIOLOGY Ce!! $y$!e ti(e Bth n"(a! an+ nep!asti$ $e!!s ha1e a g"'th $y$!e +i1i+e+ int < g"'th phases %G-, S, G= an+ M& an+ a "esting phase %G7&. Ce!! $y$!e ti(e " gene"atin ti(e, " T$, is the ti(e "e4*i"e+ t $(p!ete ne $y$!e ) $e!! g"'th an+ +i1isin. DNA is synthesi5e+ +*"ing the S phase 'ith the enti"e DNA $ntent ) the $e!! +*p!i$ate+. D*"ing G- an+ G=, n DNA synthesis $$*"s a!th*gh #th RNA an+ p"tein a"e synthesi5e+. 6hen $e!!s a"e in G- )" p"!nge+ pe"i+s ) ti(e, they a"e )ten sai+ t #e in the "esting phase " G7. The $e!! *n+e"ges (itsis +*"ing the M phase 'he"e )ina! steps ) $h"(s(e "ep!i$atin an+ seg"egatin $$*". The +*"atin ) the S2phase in h*(an t*("s is -7 t =7 h*"s. This pe"i+ is )!!'e+ #y the G=2phase, " pe"i+ ) p"epa"atin )" (itsis, in 'hi$h $e!!s $ntain a tet"ap!i+ n*(#e" ) $h"(s(es. The G=2 phase !asts n!y - t > h*"s )" (st $e!! types, 'ith (itsis itse!) !asting app",i(ate!y - h*". The t' +a*ghte" $e!!s then ente" the G-2phase, 'hse +*"atin 1a"ies )"( se1e"a! h*"s t +ays.The G-2phase a!s $an gi1e "ise t a "esting state, te"(e+ G7, in 'hi$h $e!!s a"e "e!ati1e!y ina$ti1e (eta#!i$a!!y an+ a"e "esistant t (st $he(the"ape*ti$ +"*gs.. The T$ 'i!! 1a"y 'ith the +*"atin ) the G-2phase. The )a$t"s that in)!*en$e +a*ghte" $e!!s t ente" the G7, " "esting stage, a"e nt 'e!! *n+e"st+. The a#i!ity t $a*se s*$h "esting $e!!s t "eente" the $e!! $y$!e '*!+ #e 4*ite *se)*!, sin$e p"!i)e"ating $e!!s gene"a!!y a"e ("e sensiti1e t $he(the"apy than a"e "esting $e!!s. T*(" g"'th One ) the (a:" +i))i$*!ties in t"eating $an$e" is that t*(" g"'th is *s*a!!y )a" a+1an$e+ #e)"e $an$e" is +iagnse+. Let *s s*ppse that a t*(" a"ises )"( a sing!e $e!! an+ that the g"'th is e,pnentia!, as it (ay 'e!! #e +*"ing the initia! stages. ?D*#!ing? ti(es 1a"y, #eing, )" e,a(p!e, app",i(ate!y =< h*"s 'ith B*"3itt?s !y(ph(a, = 'ee3s in the $ase ) s(e !e*3ae(ias, an+ > (nths 'ith (a((a"y $an$e"s. App",i(ate!y >7 +*#!ings '*!+ #e "e4*i"e+ t p"+*$e a $e!! (ass 'ith a +ia(ete" ) = $(, $ntaining -7 . $e!!s. S*$h a t*(" is 'ithin the !i(its ) +iagnsti$ p"$e+*"es, a!th*gh it (ight g *nnti$e+ i) it a"se in a tiss*e s*$h as the !i1e". A )*"the" -7 +*#!ings '*!+ p"+*$e -7 -= $e!!s, a t*(" (ass that is !i3e!y t #e !etha!, an+ 'hi$h '*!+ (eas*"e a#*t =7 $( in +ia(ete" i) it 'e"e ne s!i+ (ass. The pe"$entage ) the tta! n*(#e" ) $e!!s in a t*(" that a"e @$y$!ingA " a$ti1e!y +i1i+ing is "e)e""e+ t as the g"'th )"a$tin. The g"eate" the n*(#e" ) $e!!s in the "esting phase, the !'e" the g"'th )"a$tin ) the t*(". I) the g"'th )"a$tin app"a$hes - an+ the $e!! +eath "ate a"e !', the t*(" +*#!ing ti(e app",i(ates the $e!! $y$!e ti(e. Ce!! $y$!e spe$i)i$ agents a"e e))e$ti1e against t*("s 'ith high g"'th )"a$tin. Ce!! $y$!e nn2spe$i)i$ agents '*!+ #e !ess +epen+ent n a high g"'th )"a$tin )" thei" e))i$a$y. The G(pe"t5ian 3ineti$ +es$"i#es the $ha"a$te"isti$ hype"#!i$ g"'th $*"1e +isp!aye+ #y (st t*("s 'he"ein initia! g"'th is 1e"y "api+ %steep s!pe& an+ then s!'s +'n " stps %)!at $*"1e& 'hen the t*(" "ea$hes a !a"ge si5e. The tta! n*(#e" ) $e!!s in the pp*!atin is $!ini$a!!y i(p"tant #e$a*se it is an in+e, ) h' a+1an$e+ the $an$e" is an+ it $""e!ates 'ith the n"(a! )*n$tining ) "gan syste(s. As tta! n*(#e" ) $e!! in$"ease, s +es the n*(#e" ) "esistant $e!!s. La"ge t*("s (ay a!s $(p"(ise #!+ s*pp!y an+ ,ygenatin that $an in1a"ia#!y i(pai" +"*g +e!i1e"y t the t*(" $e!!s. Ce!! +eath (ay " (ay nt $$*" at the ti(e ) e,ps*"e t the +"*g. Cytt,i$ +"*gs a$t 1ia )i"st "+e" 3ineti$s an+ n!y a gi1en p"p"tin ) $e!!s +ie 'ith a gi1en t"eat(ent. Hen$e, "epeate+ +ses ) $he(the"apy (*st #e $ntin**s!y *se+ t "e+*$e the t*(" #*"+en. Ea$h ti(e the +se is "epeate+, the sa(e p"p"tin ) $e!!s an+ nt the sa(e a#s!*te n*(#e" is 3i!!e+. This "e)e"s t the @!g 3i!!A hypthesis. Int"insi$ $e!! +eath "ate is 4*ite +i))i$*!t t (eas*"e in t*("s #*t p"#a#!y (a3es a $nt"i#*tin #y s!'ing the g"'th "ate ) (any s!i+ t*("s. D"*gs Resistan$e D"*g "esistan$e is a (a:" )a$t" !i(iting the e))i$a$y ) $he(the"apy )" patients 'ith GTN. Many patients *n+e"ging $he(the"apy )ai! t "espn+ t t"eat(ent )"( the *tset 'hi!e the" patients "espn+ initia!!y, n!y t "e!apse. At the ti(e ) +iagnsis, (st t*("s a"e a!"ea+y in the !ate phase ) the G(pe"t5ian g"'th $*"1e 'ith a !' g"'th )"a$tin an+ a !ng +*#!ing ti(e. These t*("s a"e "e!ati1e!y "esistant t antinep!asti$ agents that a"e (st e))e$ti1e n a$ti1e!y $y$!ing $e!!s %3ineti$ "esistan$e&. Geneti$ "esistan$e "es*!ts )"( spntane*s (*tatins $a*sing in$"ease+ t"ansp"t ) +"*g *t ) the $e!!, +e$"ease+ a1ai!a#i!ity ) "e$ept"s )" +"*gs, 1e"p"+*$tin ) the ta"gets ) the $he(the"ape*ti$ agents " *se ) a!te"nate path'ay as s*"$e ) (eta#!ite 'hen p"i(a"y path'ay is ta"get ) +"*gs. Pha"(a$!gi$ "esistan$e $$*"s #e$a*se t*(" $e!!s a"e !$ate+ in @san$t*a"iesA an+ a"e the"e)"e nt e,pse+ t antit*(" agents. A )"( ) "esistan$e te"(e+ p!eit"pi$, " (*!ti+"*g, "esistan$e, is the (a:" )"( ) "esistan$e t a 1a"iety ) +"*gs s*$h as anth"a$y$!ines, 1in$a a!3a!i+s, etpsi+e, pa$!ita,e!, an+ +a$tin(y$in. T*(" $e!!s (ay #e$(e gene"a!!y "esistant t these +"*gs +*e t +e$"ease+ *pta3e " "etentin ) the +"*gs. The gene that $n)e"s (*!ti+"*g "esistan$e %te"(e+ (+" I& en$+es a high2(!e$*!a"2'eight (e(#"ane p"tein $a!!e+ P2g!y$p"tein, 'hi$h a$ts as a +"*g e))!*, p*(p in (any t*("s an+ n"(a! tiss*es. Pssi#!e #i$he(i$a! (e$hanis(s ) "esistan$e a"e the )!!'ingB 1.decreased drug transport into the cell C (etht"e,ate, (e!pha!an, (e$h!"etha(ine, $yta"a#ine 2.reduced drug activation- $yta"a#ine, % +e,y$yti+ine 3inase &, /2a5a$yti+ine %*"i+ine2 $yti+ine 3inase &,/2)!*"*"a$i! % *"i+ine 3inasae,"ti$ a$i+, phsph"i#sy! t"ans)e"ase, *"i+ine phph"y!ase&, 02 (e"$aptp*"ine, 02 thig*anine, % hyp,anthine g*anine, phsph"i#sy! t"ans)e"ase&, (etht"e,ate 3.increased drug or active metabolite inactivation to inactive metabolite: $yta#a"ine %$yti+ine +ea(inase& , a!! a!3y!ating agents an+ agents a$ting th"*gh )"ee "a+i$a!s % g!*tathine, (eta!!thineins&, 02(e"$aptp*"ine, 02thig*"ine 4.increased DNA repair: a!! a!3y!ating agents, antit*(" anti#iti$s, tpis(e"ase II a$ti1e +"*gs, $isp!atin 5.use of alternate patha! as source of metabolite hen primar! patha! is target of drugs: (etht"e,ate, an+ /2)!*"*"a$i! %in$"ease+ thy(i+ine, )"( sa!1age path'ay &, 02 (e"$aptp*"ine an+ 02 thig*anine % in$"ease+ sa!1age path'ay )" p*"ines & ".increased drug transport outside the cellB 1in$a a!3a!i+s, antit*(" anti#iti$s, etpsi+e % in$"ease+ P2g!y$p"tein ) the (+" gene #y a(p!i)i$atin " a$ti1atin # $.gene amplification of en%!me target or drug action: (etht"e,ate % +ihy+")!ate "e+*$tase, /2)!*"*"a$i! % thy(i+i!ate synthase& ,=2+e,y$)"(y$in% a+ensine +ea(inase & &.alteration of target to reduce drug binding: 1in$"istine %t*#*!in& , (etht"e,ate %+ihy+")!ate "e+*$tase& ,/2)!*"*"a$i! % thy(i+i!ate synthase&, hy+",y*"ea %"i#n*$!eti+e "e+*$tase &, +,"*#i$in % tpis(e"ase II & ,+a*n(y$in %tpis(e"ase II &, etpsi+e % tpis(e"ase II & P"a$ti$e ) Che(the"apy Can$e"s $an #e "ega"+e+ as pp*!atins ) $e!!s *n+e"ging spntane*s (*tatins. The pp*!atin #e$(es in$"easing!y hete"gene*s as the t*(" g"'s an+ in$"easing n*(#e"s ) (*tatins $$*". T*("s ) the sa(e type an+ si5e 'i!! 1a"y in thei" "espnsi1eness t the"apy #e$a*se ) the $han$e $$*""en$es ) +"*g "esistant (*tatins +*"ing t*(" g"'th. Ass*(ing the sa(e initia! +"*g sensiti1ity, s(a!!e" t*("s a"e gene"a!!y ("e $*"a#!e than !a"ge" t*("s #e$a*se ) the in$"ease+ p"#a#i!ity ) +"*g2"esistant (*tatins in the !a"ge" t*("s. The"e)"e, the"apy ea"!ie" in the $*"se ) t*(" g"'th sh*!+ in$"ease the $han$e )" $*"e. C(#inatin $he(the"apy is )ten ("e e))e$ti1e than t"eat(ent 'ith sing!e +"*gs. T*("s that a"e "esistant t +"*gs )"( the *tset 'i!! a!'ays ha1e a !a"ge!y +"*g2"esistant pp*!atin an+ 'i!! #e "e)"a$t"y t t"eat(ent. C(#inatin ) +"*gs is )"e4*ent!y ("e e))e$ti1e in p"+*$ing "espnses an+ p"!nging !i)e than the sa(e +"*gs *se+ se4*entia!!y. D"*g $(#inatin sh*!+ #e gi1en at "eg*!a" inte"1a!s 'ith the sh"test pssi#!e t"eat(ent )"ee inte"1a! #et'een t"eat(ent $y$!es t p"e1ent nset ) "esistan$e. The pti(a! +se an+ s$he+*!e sh*!+ #e )!!'e+ at a!! ti(es. The )!!'ing p"in$ip!es a"e i(p"tant )" se!e$ting app"p"iate +"*gs t #e *se+ in $(#inatin $he(the"apy. a. Ea$h +"*g sh*!+ #e a$ti1e against the pa"ti$*!a" t*(" 'hen *se+ sing!y. #. The +"*gs sh*!+ ha1e +i))e"ent (e$hanis(s ) a$tin. $. C"ss2"esistan$e #et'een +"*gs sh*!+ #e (ini(a!. +. The +"*gs sh*!+ ha1e +i))e"ent +se !i(iting t,i$ity. Che(the"apy $(#ine+ 'ith the" (+a!ities ) t"eat(ent s*$h as s*"ge"y an+ "a+iatin the"apy (ay #e ("e e))e$ti1e in s(e $ases. C(#ining (+a!ities is gene"a!!y *se+ 'hen "es*!ts )"( a sing!e t"eat(ent (eth+ a"e p".
TODICITY OF CANCER CHEMOTHERAPE;TIC AGENTS Mst a1ai!a#!e anti$an$e" +"*gs, pa"ti$*!a"!y thse that a"e ?$ytt,i$?, a))e$t n!y ne $ha"a$te"isti$ aspe$t ) $an$e" $e!! #i!gy2$e!! +i1isin2#*t ha1e n spe$i)i$ inhi#it"y e))e$t n in1asi1eness, the !ss ) +i))e"entiatin, " the ten+en$y t (etastasise. In (any $ases, the antip"!i)e"ati1e a$tin "es*!ts )"( an a$tin +*"ing S phase ) the $e!! $y$!e, an+ the "es*!tant +a(age t DNA initiates apptsis. F*"the"("e, #e$a*se thei" (ain ta"get is $e!! +i1isin, they 'i!! a))e$t a!! "api+!y +i1i+ing n"(a! tiss*es, an+ th*s they a"e !i3e!y t p"+*$e, t a g"eate" " !esse" e,tent, the )!!'ing gene"a! t,i$ e))e$tsB bone marro to'icit! %(ye!s*pp"essin& 'ith +e$"ease+ !e*$$yte p"+*$tin an+ th*s +e$"ease+ "esistan$e t in)e$tin impaired ound healing loss of hair %a!pe$ia& +a(age t gastrointestinal epithelium depression of groth in $hi!+"en sterilit! teratogenicit!. Mst ) these t,i$ities a"e "e1e"si#!e n$e the $he(the"ape*ti$ "egi(en is +is$ntin*e+. CALC;LATION OF DOSAGE AND DOSE SCHED;LING D"*g +ses a"e (st )ten $a!$*!ate+ a$$"+ing t the patientEs #+y s*")a$e a"ea %(ete" s4*a"e+ " ( = & an+ $$asina!!y #y 'eight %3i!g"a(s&. The patientEs #+y s*")a$e a"ea is +ete"(ine+ #y height an+ 'eight n(g"a(s. Dse #ase+ n s*")a$e a"eas is p"e)e""e+ 1e" that *sing 'eight #e$a*se ) !ess s*")a$e a"ea $hanges +*"ing the $*"se ) $he(the"apy. This a!!'s )" a ("e $nsistent +e!i1e"y ) #asi$a!!y the sa(e $n$ent"atin ) +"*g +*"ing the $*"se ) t"eat(ent. It is a!'ays #est t sta"t $he(the"apy 'hen the t*(" #*"+en is s(a!! sin$e these t*("s ha1e a highe" g"'th )"a$tin C $e!!s a"e a$ti1e!y +i1i+ing an+ a"e th*s, ("e s*s$epti#!e t the $ytt,i$ e))e$ts ) the antinep!asti$ agents. S*$$ee+ing +ses ) the"apy a"e *s*a!!y a+(iniste"e+ as sn as the hst "e$1e"s )"( the p"e1i*s $*"se as "epetiti1e a+(inist"atin ) the +"*g $an p"+*$e a !ga"ith(i$ !ss ) t*(" $e!!s 'ith*t pe"(itting the t*(" $e!!s t a$4*i"e "esistan$e. D"*gs a"e )ten gi1en in !a"ge +ses inte"(ittent!y in se1e"a! $*"ses 'ith inte"1a!s ) =2> 'ee3s #et'een $*"se "athe" than in s(a!! +ses $ntin**s!y #e$a*se this "egi(en pe"(its "egene"atin ) the #ne (a""'. It has a!s #een sh'n that the sa(e tta! +se ) an agent is ("e e))e$ti1e 'hen gi1en in ne " t' !a"ge +ses than in (*!tip!e s(a!! +ses. INDIFID;AL ANTI NEOPLASTIC AGENTS COMMONLY ;SED IN THE TREATMENT OF GESTATIONAL TROPHOBLASTIC NEOPLASIA I. A!3y!ating Agents A. Cy$!phspha(i+e This a!3y!ating +"*g is $((n!y *se+ in $(#inatin 'ith (etht"e,ate an+ a$tin(y$in D %MAC& in the t"eat(ent ) GTD. It is *se+ as a $(pnent ) EMA2CO %Etpsi+e, Metht"e,ate, A$tin(y$in D, Cy$!phspha(i+e, On$1in& in the t"eat(ent ) high2"is3 GTN. A)te" $n1e"sin t its a$ti1e (eta#!ite in the !i1e", it inte")e"es 'ith DNA "ep!i$atin an+ RNA t"ans$"iptin "es*!ting in +is"*ptin ) n*$!ei$ a$i+ )*n$tin. Its phsph"y!ating p"pe"ties enhan$es its $ytt,i$ a$ti1ity an+ is *se)*! )" p*"ging !e*3e(ia an+ !y(ph(a $e!!s in #ne (a""' *n+e"ging a*t!g*s t"ansp!antatin p"g"a(. It (ay #e a+(iniste"e+ "a!!y " int"a1en*s!y %IF& 'ith a p!as(a ha!)2!i)e ) -0 h*"s. G78 ) the a+(iniste"e+ +se is e!i(inate+ #y (eta#!is( 'ith >02..8 e,$"ete+ in the *"ine 'ithin <G h*"s as an *n$hange+ +"*g. Its (eta#!ites a"e +ist"i#*te+ 'i+e!y th"*gh*t the #+y an+ ente" the CNS. H'e1e", they + nt "ea$h $n$ent"atins s*))i$ient t t"eat CNS !e*3e(ia. The a$$*(*!atin ) the (eta#!ite a$"!ein in the #!a++e" $$asina!!y $a*ses he(""hagi$ $ystitis. This (ay #e a1i+e+ #y 1ig"*s hy+"atin. Dis$ntin*atin ) t"eat(ent sh*!+ #e $nsi+e"e+ i) this $(p!i$atin ens*es. H'e1e", the (a:" +se2!i(iting t,i$ity sti!! "e(ains t #e (ye!s*pp"essin. F" patients 'h +e1e!p in)e$tins, inte""*ptin " "e+*$tin ) +"*g +sage is +ne #e$a*se ) the i((*ns*pp"essi1e p"pe"ty ) the +"*g. Othe" t,i$ities in$!*+e na*sea an+ 1(iting, (*$sitis, p*!(na"y )i#"sis, "a"e!y $a"+ia$ t,i$ity an+ inapp"p"iate ADH se$"etin at high +ses. Cn$*""ent *se ) Phen#a"#ita!, "i)a(pin, a!!p*"in! " thia5i+e +i*"eti$s (ay in$"ease t,i$ity. Cy$!phspha(i+e (ay a!s p"!ng ne*"(*s$*!a" #!$3a+e )"( s*$$iny!$h!ine. B. Cisp!atin Cisp!atin is (ain!y *se+ as a $(pnent ) (*!ti2agent "egi(ens in$!*+ing EMA2EP %Etspsi+e, Metht"e,ate, A$tin(y$in D, Etpsi+e, Cisp!atin& in the t"eat(ent ) high2"is3 GTN. It is a p!atin*(2#ase+ +"*g. It is a "ea$ti1e (!e$*!e 'hi$h $"ss!in3s DNA #y )"(ing inte" an+ int"a st"an+ !in3s. Resistan$e has #een att"i#*te+ t 1a"i*s (e$hanis(s s*$h as +e$"ease+ *pta3e, an in$"ease in the "epai" ) DNA !esins, an+ in$"ease in the (eta!2#in+ing p"tein (eta!!thinine. This +"*g is a+(iniste"e+ int"a1en*s!y 'ith )"$e+ hy+"atin. F!!'ing a+(inist"atin, ("e than .78 ) the +"*g is $1a!ent!y #*n+ t p"tein, pe"sisting in the se"*( )" !ng pe"i+s ) ti(e. D*e t this p"tein #in+ing, high a(*nts ) $isp!atin a"e )*n+ in the !i1e", 3i+ney, intestine an+ testes 'ith p" CNS penet"atin. It has an initia! e!i(inatin ha!)2!i)e in p!as(a ) =/2/7 (in*tes. =72<78 ) the +se is e,$"ete+ in the *"ine 'ithin the )i"st )e' +ays a)te" a+(inist"atin. The +se !i(iting t,i$ity is neph"t,i$ity +*e t t*#*!a" in:*"y 'hi$h (ay #e a1i+e+ #y 1ig"*s hy+"atin #e)"e an+ a)te" +"*g a+(inist"atin. >8 s+i*( $h!"i+e (ay #e gi1en t +e$"ease a$ti1atin ) this $(p*n+ an+ "ena! t,i$ity. F" thse patients "e$ei1ing (*!tip!e $*"ses ) the +"*g, ne*"t,i$ity s*$h as hea"ing i(pai"(ent, pe"iphe"a! ne*"pathy an+ e(esis (ay #e a p"#!e(. E!e$t"!yte +ist*"#an$es (ay #e +*e t $isp!atin Cin+*$e+ "ena! t*#*!a" +ys)*n$tin. Na*sea an+ 1(iting a"e a!s $((n!y #se"1e+ 'hi$h (ay #e t"eate+ p"phy!a$ti$a!!y 'ith antie(eti$s $(#ine+ 'ith $"ti$ste"i+s. C. I)s)a(i+e I)s)a(i+e is an a!3y!ating agent *se+ sing!y " in $(#inatin 'ith the" agents in the t"eat(ent ) "e)"a$t"y GTN. It is a $e!! $y$!e phase nnspe$i)i$ agent 'hi$h, a)te" $n1e"sin t a$ti1e $(p*n+s, inte")e"es 'ith DNA "ep!i$atin an+ RNA t"ans$"iptin *!ti(ate!y +is"*pting p"tein synthesis. Me$hanis( ) "esistan$e )" this agent (ain!y in1!1e (*!ti2+"*g "esistan$e genes. The +"*g is n!y a+(iniste"e+ IF +*e t the *na$$epta#!e in$i+en$e ) ne*"t,i$ity 'hen a+(iniste"e+ "a!!y. It "e4*i"es (eta#!i$ a$ti1atin #y (i$"s(a! !i1e" en5y(es t p"+*$e #i!gi$a!!y a$ti1e (eta#!ites. It is e,tensi1e!y +ist"i#*te+ t tiss*es in the #+y. At sing!e +ses ) >.G2/.7 gH(=, +"*g $n$ent"atins +e$ay #iphasi$a!!y an+ the (ean te"(ina! ha!) !i)e is -/ h*"s. At +ses -.02=.< gH(=H+ay, +e$ay is (ne,pnentia! an+ the (ean te"(ina! ha!) !i)e is I h*"s. -=2-G8 ) the +se is e,$"ete+ in the *"ine *n$hange+ 'ithin I= h*"s. The +se2!i(iting t,i$ities in$!*+e (ye!s*pp"essin an+ *"t,i$ity. Dse )"a$tinatin, 1ig"*s hy+"atin an+ the *se ) a p"ete$t" s*$h as (esna (ay signi)i$ant!y +e$"ease the "is3 ) +e1e!ping he(""hagi$ $ystitis. Othe" signi)i$ant si+e e))e$ts in$!*+e na*sea, 1(iting, a!pe$ia an+ CNS t,i$ities. These t,i$ities (ay #e enhan$e+ 'hen $2 a+(iniste"e+ 'ith a!!p*"in! " Phen#a"#ita!. II. Cytt,i$ Anti#iti$ A$tin(y$in D A$tin(y$in D is *se+ as a sing!e agent 'hen Metht"e,ate %MTD& $annt #e *se+ #e$a*se ) hepati$ " "ena! i(pai"(ent, i) the"e a"e !a"ge e))*sins, !a"ge the$a !*tein $ysts a"e p"esent " 'hen a patient sh's "esistan$e t it. Its e))i$a$y is $(pa"a#!e t MTD 'hen gi1en t app"p"iate s*#set ) patients. It is a!s gi1en as a $(pnent ) the EMA2CO an+ EMA2EP "egi(en. C!assi)ie+ as a $ytt,i$ anti#iti$, it a$ts n a!! phases ) the $e!! $y$!e. It inhi#its DNA +epen+ent RNA synthesis #y )"(ing a $(p!e, 'ith DNA. It inte"$a!ates 'ith g*anine "esi+*es th*s i(pai"ing the te(p!ate a$ti1ity ) DNA. It is a+(iniste"e+ IF as it is p"!y a#s"#e+ 'hen gi1en "a!!y. The +"*g is 'i+e!y +ist"i#*te+ th"*gh*t the #+y #*t +es nt $"ss the #!+ #"ain #a""ie". One2ha!) ) the +sage is e,$"ete+ in the *"ine, the "e(ain+e" ) the +"*g is e,$"ete+ in the )e$es an+ )*"the" (eta#!i5e+ #y the !i1e". Its e!i(inatin ha!) !i)e is <2-- h*"s. Ea"!y a+1e"se e))e$ts in$!*+e na*sea an+ 1(iting 'hi$h $((n!y #egin 'ithin a )e' h*"s ) t"eat(ent an+ (ay !ast as !ng as =< h*"s. H'e1e", the (a:" +se !i(iting t,i$ities a"e !e*3penia an+ th"(#$ytpenia. These he(at!gi$ t,i$ities "ea$h a na+i" =2> 'ee3s a)te" a $*"se ) $he(the"apy. GI t,i$ities in$!*+e p"$titis, +ia""hea, g!ssitis, $hei!itis an+ (*$sitis. @Ra+iatin "e$a!!A (ay a!s $$*" 'he"e the"e is s3in i""itatin " s(eti(es ne$"sis, 1e" p"e1i*s!y i""a+iate+ a"eas. A!pe$ia an+ se1e"e +e"(at!gi$ t,i$ities (ay $$asina!!y #e seen. The +"*g sh*!+ #e gi1en 'ith e,t"a1asatin p"e$a*tins as this (ay "es*!t in se1e"e pain, s'e!!ing an+ ne$"sis. III. Anti(eta#!ites A. Metht"e,ate %MTD& Metht"e,ate is *se+ as a sing!e agent in the t"eat(ent ) nn2(etastati$ an+ !'2 "is3 GTN. St*+ies ha1e sh'n -778 s*staine+ "e(issin 'ith the *se ) this sing!e agent in p"pe"!y se!e$te+ $ases. It is a!s *se+ as a $(pnent ) (*!ti2agent the"apies in$!*+ing EMA2 CO an+ EMA2EP in the t"eat(ent ) high2"is3 GTN. Metht"e,ate is S2phase spe$i)i$. It inhi#its +ihy+")!ate "e+*$tase 'hi$h #!$3s the "e+*$tin ) +ihy+")!ate t tet"ahy+")!ate. This #!$3age in t*"n inhi#its the )"(atin ) thy(i+y!ates an+ p*"ines an+ a""ests DNA, RNA an+ p"tein synthesis. A$4*i"e+ "esistan$e t MTD (ay #e +*e t se1e"a! (e$hanis(s in$!*+ing in$"ease+ $n$ent"atins ) DHFR as a "es*!t ) gene a(p!i)i$atin, +e)e$ti1e p!yg!*ta(y!atin, i(pai"e+ *pta3e, " an a!te"atin in the ta"get en5y(e, DHFR. Dses *p t <7 (gH( = a"e "ea+i!y a#s"#e+ )"( the gast"intestina! t"a$t. Pea3 p!as(a !e1e!s $$*" 7./ t = h*"s a)te" "a! +sing. At highe" +ses, in$(p!ete a#s"ptin $$*"s an+ it has t #e gi1en int"a1en*s!y, int"a(*s$*!a"!y " s*#$*tane*s. A)te" IF a+(inist"atin, the +"*g is +ist"i#*te+ in a t"iphasi$ (anne". The "api+ +ist"i#*ti1e phase %t-H= J>72</ (in& is )!!'e+ #y a se$n+ phase 'hi$h "e)!e$ts the "ena! $!ea"an$e %t-H= J =.> h"& then a te"(ina! phase 'ith a t-H= ) 02=7 h*"s. In sit*atins 'he"e the"e is e,pansin ) #+y spa$es, these spa$es a$t as +"*g +epts e1ent*a!!y !ea+ing t p"!nge+ high $n$ent"atin an+ ("e se1e"e t,i$ity. The $n$ent"atin in the CSF is n!y >8 ) that in the syste(i$ $i"$*!atin at stea+y state #*t high +ses %K-./ g(H( = & )!!'e+ #y !e*$1"in "es$*e a$hie1es $ytt,i$ $n$ent"atin in the CNS. It (ay a!s #e gi1en int"athe$a!!y in $ases 'he"e the"e is e1i+en$e ) #"ain (etastasis. Ha!) ) the +"*g is #*n+ t p!as(a p"tein an+ (st ) the a#s"#e+ +"*g is e!i(inate+ *n$hange+ in the *"ine 'ithin <G h*"s. Thse "e$ei1ing high +ses a"e at "is3 )" neph"t,i$ity +*e t a$$*(*!atin ) t,i$ (eta#!ites espe$ia!!y I2hy+",y(etht"e,ate. The +se !i(iting t,i$ities ) MTD a"e (ye!s*pp"essin an+ GI t,i$ity. These )ten appea" I2-7 +ays a)te" t"eat(ent. Ea"!y sign ) GI t"a$t t,i$ity is (*$sitis an+ se1e"e t,i$ity (ay #e (ani)este+ #y +ia""hea, *!$e"atin an+ #!ee+ing. Less $((n t,i$ e))e$ts in$!*+e s3in "ash, p!e*"itis an+ hepatitis. Rena! t,i$ity is !ess $((n 'ith $n1entina! +ses ) MTD #*t is a p"#!e( 'ith high +se "egi(en %K7./ g(H( = &. A!3a!ini5atin ) the *"ine an+ hy+"atin as 'e!! as (nit"ing MTD se"*( $n$ent"atin a"e i(p"tant (eas*"es t a1i+ an+ +ete$t this p"#!e(. Le*$1"in , a tet"ahy+")!i$ a$i+ +e"i1ati1e, is the anti+te *se+ t t"eat the ptentia! t,i$ e))e$ts ) MTD 1e"+se. It is a!s *se+ as pa"t ) high +se MTD "egi(ens as p!anne+ @"es$*eA. Se1e"a! inte"a$tins 'ith +"*gs sh*!+ #e nte+ 'hen *sing MTD. As it is pa"t!y #*n+ t se"*( p"teins, it (ay #e +isp!a$e+ #y $e"tain +"*gs s*$h as sa!i$y!ates, s*!)na(i+es %in$!*+ing $2t"i(,a5!e&, s*!)ny!*"eas, phenytin, pheny!#*ta5ne, tet"a$y$!ines, $h!"a(pheni$! an+ a(in#en5i+ a$i+, in$"easing its t,i$ity. 6ea3 "gani$ a$i+s (ay +e!ay its "ena! e,$"etin. NSAID (ay a!s inhi#it "ena! e!i(inatin pssi#!y #y +e$"easing "ena! pe")*sin. Peni$i!!ins (ay inhi#it se$"etin ) the +"*g an+ MTD (ay a!s +e$"ease $!ea"an$e ) thephy!!ine. B. /2F!*"*"a$i! This +"*g has #een e(p!ye+ as a sing!e agent in the t"eat(ent ) GTD in the Fa" East. /2F; a!s a$ts n the S phase ) the $e!! $y$!e. It is $n1e"te+ t /2)!*"+e,y*"i+y!ate %/2 F+;MP& that inhi#its the en5y(e thy(i+y!ate synthetase 'hi$h #!$3s DNA synthesis. A$tin ) / F; (ay #e (+*!ate+ #y the p"esen$e ) e,$ess #ia$ti1e )!ates 'hi$h ens*"e (a,i(a! te"na"y2$(p!e, )"(atin an+ a!s "eta"+s +isass$iatin ) F+;MP )"( the $(p!e, ) F+;MP, N / ,N -7 C(ethy!enetet"ahy+")!ate an+ thy(i+y!ate synthase. /2F; is a+(iniste"e+ int"a1en*s!y as "a! a#s"ptin ) the +"*g is *np"e+i$ta#!e an+ in$(p!ete. The +"*g is 'i+e!y +ist"i#*te+ in the tiss*es )!!'ing IF a+(inist"atin, 'ith -78 #eing p"tein2#*n+. It "ea+i!y ente"s the CSF an+ $n$ent"atin K 7.7- (M is s*staine+ )" *p t -= h*"s )!!'ing $n1entina! +ses. It is (eta#!i5e+ (ain!y in the !i1e" an+ s(a!! a(*nts a"e e,$"ete+ *n$hange+ in the *"ine. P!as(a $!ea"an$e is "api+ an+ *"ina"y e!i(inatin a(*nts t n!y /2-78 ) the +se in =< h*"s. A!th*gh +eg"a+atin $$*"s p"i(a"i!y in the !i1e", n +sage a+:*st(ent is ne$essa"y in thse 'ith i(pai"e+ !i1e" )*n$tin #e$a*se ) e,t"ahepati$ +eg"a+atin an+ the a#*n+an$e ) the en5y(e +ihy+"py"i(i+ine +ehy+"genase in the !i1e". The (a:" t,i$ity )"( in)*sins ) /2F; is gast"intestina! i""itatin 'hi!e #!*s t"eat(ent *s*a!!y p"+*$es he(at!gi$ p"#!e(s in$!*+ing !e*3penia an+ th"(#$ytpenia. St(atitis an+ +ia""hea *s*a!!y $$*"s <2I +ays a)te" t"eat(ent an+ )*"the" t"eat(ent sh*!+ #e 'ithhe!+ *nti! the"e is "e$1e"y. Le*3penia an+ th"(#$ytpenia $$*"s I2-7 +ays a)te" a sing!e +se " a /2+ay $*"se ) the +"*g an+ "e$1e"y *s*a!!y $$*"s a)te" = 'ee3s. Less $((n a+1e"se e))e$ts a"e s3in "ash, $e"e#e!!a" sy(pt(s, $n:*n$ti1itis an+ tea"ing, a!pe$ia an+ $a"+ia$ t,i$ity. Le*$1"in enhan$es the t,i$ity ) )!*"*"a$i! #y (a,i(i5ing te"na"y2 $(p!e, )"(atin in (a!ignant $e!!s. IF. Othe" Agents A. Etpsi+e Etpsi+e has #een *se+ #th as a sing!e agent an+ as a $(pnent ) EMA2CO an+ EMA2EP in the t"eat(ent ) GTN. It is a syntheti$ +e"i1ati1e ) p+phy!!in, a $(p*n+ t t,i$ )" syste(i$ *se. It is a $e!! $y$!e spe$i)i$ agent a$ting in the !ate S phase " G= phase. Etpsi+e $a*ses e"""s in DNA synthesis #y inhi#iting tpis(e"ase II the"e#y p"+*$ing sing!e st"an+ #"ea3s in the DNA. Resistan$e (ay $$*" 1ia the (*!ti+"*g "esistan$e phentype " as a $nse4*en$e ) an a!te"atin in tpis(e"ase II 'hi$h e1ent*a!!y !ea+s t +e$"ease+ #in+ing ) the +"*g. Etpsi+e (ay #e a+(iniste"e+ "a!!y " int"a1en*s!y. 6hen gi1en "a!!y, ha!) ) the +se is a#s"#e+. A)te" IF a+(inist"atin, The"e is a #iphasi$ $!ea"an$e 'hen gi1en int"a1en*s!y 'ith a te"(ina! ha!)2!i)e ) 02G h*"s gi1en "ena! )*n$tin is n"(a!. App",i(ate!y ne2ha!) ) the +sage is e,$"ete+ in the *"ine, 'ith ne thi"+ as (eta#!ite. The "e(ain+e" ) the +"*g is e,$"ete+ in the )e$es an+ )*"the" (eta#!i5e+ #y the !i1e". Etpsi+e sh*!+ #e a+(iniste"e+ 1e" a >7 (in*te pe"i+ 'hen #eing gi1en int"a1en*s!y t a1i+ hyptensin. Na*sea an+ 1(iting a!s $((n!y $$*"s )!!'ing IF a+(inist"atin. The (a:" t,i$ity is !e*3penia. This #eing the $ase, in1estigatins 'he"ein it is gi1en at high +ses )!!'e+ #y (a""' t"ansp!antatin a"e *n+e" 'ay. ;se ) this +"*g as a sing!e agent is s(e'hat "est"i$te+ #e$a*se ) appea"an$e ) se$n+ t*("s. B. On$1in On$1in " 1in$"istine is *se+ as pa"t ) the (*!ti2agent "egi(en EMA2CO in the t"eat(ent ) high2"is3 GTN. It is a 1in$a a!3a!i+ is!ate+ )"( the !ea1es ) the Ma+agas$a" pe"i'in3!e p!ant. It is $e!! $y$!e spe$i)i$ #eing a (itti$ inhi#it". It #in+s spe$i)i$a!!y t t*#*!in an+ #!$3s the a#i!ity ) the p"tein t p!y(e"i5e int (i"$t*#*!es. Me$hanis(s ) "esistan$e t this +"*g in$!*+e an a!te"atin in the st"*$t*"e ) t*#*!in "es*!ting in +e$"ease+ #in+ing ) the +"*g an+ the e(e"gen$e ) the (*!ti+"*g "esistan$e phentype 'hi$h "es*!ts in in$"ease+ +"*g e))!*,. It is gi1en int"a1en*s!y as "a! a#s"ptin ) the +"*g is *np"e+i$ta#!e. It is 1e"y i""itating an+ sh*!+ nt #e gi1en int"a(*s$*!a"!y, s*#$*tane*s!y " int"athe$a!!y. Int"athe$a! in:e$tin is in1a"ia#!y )ata!. A)te" IF a+(inist"atin, it is "api+!y an+ appa"ent!y 'i+e!y +ist"i#*te+. Fin$"istine +isappea"s )"( the p!as(a 'ith a ha!)2!i)e ) -0< (in*tes. H'e1e", 1in$"istine an+ its (eta#!ites $"ss the #!+ #"ain #a""ie" p"!y a)te" IF in:e$tin. A!(st I78 ) a +se is (eta#!i5e+ in the !i1e" an+ e,$"ete+ in the )e$es. A /78 +e$"ease in +se is "e$((en+e+ )" thse patients 'ith a #i!i"*#in $n$ent"atin K> (gH+! #*t n +e$"ease in +se is "e$((en+e+ )" "ena! )*n$tin i(pai"(ent. The +se !i(iting t,i$ity ) 1in$a a!3a!i+s is ne*"t,i$ity. Initia! signs that '*!+ ne$essitate +is$ntin*atin " +e$"ease in +sage in$!*+e pa"esthesias ) the )inge"s an+ !'e" e,t"e(ities an+ !ss ) +eep ten+n "e)!e,es. At high +ses %K> (g tta! sing!e +se& a*tn(i$ ne*"pathies s*$h as #stipatin an+ pa"a!yti$ i!e*s (ay #e seen. O$$asina!!y, $"ania! ne"1e pa!sies an+ se1e"e :a' pain a"e nte+. Mt" p"#!e(s i(p"1e !ess "api+!y than sens"y $hanges an+ "e)!e, a#n"(a!ities an+ (ay #e i""e1e"si#!e. Se1e"a! inte"a$tins (ay $$*" 'hen $2a+(iniste"e+ 'ith s(e +"*gs. It"a$na5!e sh*!+ nt #e *se+ tgethe" 'ith 1in$"istine. This $(#inatin (ay $a*se ea"!ie" " in$"ease+ se1e"ity ) ne*"(*s$*!a" a+1e"se e))e$ts. Ott,i$ +"*gs $an a!s a*g(ent hea"ing i(pai"(ent )"( eighth $"ania! ne"1e in:*"y. A#s"ptin ) phenytin (ay #e +e$"ease+ an+H" in$"ease+ (eta#!is( ) phenytin (ay $$*". C. Pa$!ita,e! Pa$!ita,e! is *se+ sing!y " in $(#inatin 'ith the" agents s*$h as $isp!atin (ain!y in "e)"a$t"y GTN *n"espnsi1e t the EMA2CO "egi(en. It sta#i!i5es (i$"t*#*!es inte")e"ing 'ith thei" #"ea3+'n +*"ing (itsis. It a!s in+*$es apptsis #y #in+ing t B$!2= 'hi$h n"(a!!y ha!ts apptsis. Me$hanis(s ) "esistan$e t Pa$!ita,e! in$!*+e 1e"e,p"essin ) MDR2- gene, (!e$*!a" $hanges in the ta"get (!e$*!e, $hanges in apptti$ "eg*!at"y an+ (itti$ $he$3pint p"teins an+ $hanges in the !ipi+ $(psitin an+ 1e"e,p"essin ) IL20. Pa$!ita,e! is a+(iniste"e+ int"a1en*s!y. It e,hi#its e,tensi1e p"tein #in+ing 'ith as (*$h as G.2.G8 #eing p"tein2#*n+. It is (ain!y (eta#!i5e+ in the !i1e" 'ith !ess than -78 ) the +"*g e,$"ete+ *n$hange+ in *"ine. The +se2!i(iting t,i$ity ) Pa$!ita,e! a"e its he(at!gi$ e))e$ts. Othe" signi)i$ant e))e$ts in$!*+e na*sea an+ 1(iting, !ss ) appetite, thinning ) hai", nai! $hanges, :int pains, an+ pa"esthesias. Cn$*""ent *se ) 3et$na5!e, 1e"apa(i!, 4*ini+ine, $y$!sp"ine, +ia5epa( ,+e,a(ethasne, tenipsi+e, etpsi+e an+ 1in$"istine (ay in$"ease the "is3 ) se"i*s t,i$ity. Ta#!e. Antinep!asti$ Agents ;se+ in The T"eat(ent ) GTN Drug Mechanism of Action Dose-limiting Toxicity Pharmacokinetics Drug Interactions Cyclophosphamide Cell cycle phase nonspecific Interferes with DNA replication and NA transcription Myelosuppression !emorrhagic cystitis A"sorption# a"sor"ed orally and intra$enously Distri"ution# widely distri"uted enters CN% Meta"olism# &xcreted in the urine Pheno"ar"ital ifampin Allopurinol !alf 'ife# () hr Cisplatin Cell cycle phase non-specific Inhi"its DNA synthesis "y cross-linking parent DNA strands Nephrotoxicity A"sorption# administered intra$enously Distri"ution# widely distri"uted Meta"olism# excreted in the urine !alf 'ife# *+-+, min Aminoglyosides 'oop diuretics Phenytoin Amphotericin - Ifosfamide Cell cycle phase nonspecific Interferes with DNA replication and NA transcription Myelosuppression .rotoxicity A"sorption# administered intra$enously Distri"ution# widely distri"uted Meta"olism# Meta"oli/ed "y li$er to acti$e compounds !alf 'ife# (+ hr Allopurinol Pheno"ar"ital 0ther antineoplastics Actinomycin D Cell cycle phase nonspecific Inhi"its NA synthesis "y forming a complex with DNA !ematologic A"sorption# poorly a"sor"ed orally Distri"ution# widely distri"uted after I1 administration2 does not cross "lood-"rain "arrier Meta"olism# most of the a"sor"ed drug is eliminated unchanged in "ile and urine !alf 'ife# 3-(( hr 0ther antineoplastic agents Methotrexate %-phase specific Inhi"its dihydrofolate reductase !ematologic 4astrointestinal A"sorption# Doses up to 3, mg5m * are readily a"sor"ed from the gastrointestinal tract Distri"ution# widely distri"uted Meta"olism# most of the a"sor"ed drug is eliminated unchanged in urine !alf 'ife# 6-(, hr 7low dose8 9-(+ hr 7high dose8 %alicylates N%AIDs %ulfonylureas Trimethoprim5sulfamethoxa/ole Tetracyclines Pro"enecid Chloramphenicol A/athioprine etinoids +-:luorouracil %-phase specific Inhi"its thymidylate synthetase 4astrointestinal !ematologic A"sorption# oral a"sorption unpredicta"le Distri"ution# widely distri"uted Meta"olism# hepatic with small amounts excreted unchanged in urine !alf 'ife# *, hr 0ther antineoplastic agents &toposide Acts on % and 4* phase Interacts with topoisomerase II !ematologic A"sorption# !alf of dose a"sor"ed when gi$en orally Distri"ution# rapidly distri"uted2 poorly enters C%: Meta"olism# 0ne-half of the dosage is excreted in the urine2 the remainder of the drug is excreted in the feces and further meta"oli/ed "y the li$er !alf 'ife# )-9 hr Antineoplastic agents 0nco$in 71incristine8 M-phase specific Arrests metaphase "y "inding to proteins of mitotic spindle Neurotoxicity A"sorption# administered intra$enously Distri"ution# rapidly and widely distri"uted Meta"olism# Meta"oli/ed "y li$er and eliminated in feces $ia "iliary excretion !alf 'ife# ()3 min Mitomycin '-Asparaginase Phenytoin Itracona/ole Paclitaxel M-phase specific Interferes with normal microtu"ule function !ematologic A"sorption# administered intra$enously Distri"ution# 9;-;,< protein-"ound Meta"olism# Meta"oli/ed "y li$er 2 =(,< excreted unchanged in urine !alf 'ife# (6-+* hr >etocona/ole 1erapamil ?uinidine Cyclosporine Dia/epam Dexamethasone Teniposide &toposide 1incristine TECHNIL;ES FOR DEALING 6ITH EMESIS AND MYELOS;PPRESSION E(esis an+ (ye!s*pp"essin a"e $((n e))e$ts ) antinep!asti$ agents that )"e4*ent!y !i(it thei" *se. E(esis $nstit*tes an in#*i!t +ete""ent t patient $(p!ian$e an+ is a pa"ti$*!a" p"#!e( 'ith the *se ) $isp!atin as 'e!! as in t"eat(ent "egi(ens *ti!i5ing a!3y!ating agents. The e(eti$ e))e$ts ) these agents $an #e (ini(i5e+ 'ith the *se ) antie(eti$ agents. E))e$ti1e antie(eti$ agents a1ai!a#!e in$!*+e (et$!p"a(i+e 'hi$h is gi1en int"a1en*s!y, +e,a(ethasne a!ne " in $(#inatin 'ith (et$!p"a(i+e , !"a5epa( an+H" +iphenhy+"a(ine. / HT> "e$ept" antagnists s*$h as n+anset"n " g"anesit"n ha1e p"1e+, in +*#!e #!in+ $!ini$a! t"ia!s, t #e high!y e))e$ti1e against $he(the"apy in+*$e+ na*sea an+ 1(iting. Mye!s*pp"essin is the +se2!i(iting t,i$ity ) (st antinep!asti$ agents. Se1e"a! te$hni4*es ha1e #een t"ie+ t (anage this p"#!e(. S(e ) the "egi(ens *se+ t 1e"$(e this p"#!e( in$!*+e "e(1ing s(e ) the patientEs #ne (a""' p"i" t a+(inist"atin ) $he(the"apy an+ "ep!a$ing it a)te"'a"+s an+ the *se ) $!ny sti(*!ating agents s*$h as G2 CSF 'hi$h is a!s e))e$ti1e in s(e $ases. An a"ea ) $*""ent in1estigatin is the int"+*$tin int the e,t"a$te+ #ne (a""', ) the (*tate+ gene 'hi$h $n)e"s (*!ti2+"*g "esistan$e, s that 'hen "ep!a$e+, the (a""' $e!!s an+ nt the $an$e" $e!!s 'i!! #e "esistant t the antip"!i)e"ati1e a$tin ) the antinep!asti$ agents.
CLINICAL RESPONSE TO THERAPY Figi!an$e in (nit"ing "espnse t $he(the"ape*ti$ "egi(en is $"*$ia! in "+e" t *ti!i5e the #est pssi#!e $(#inatin ) antinep!asti$ agents. The +e1e!p(ent ) "esistan$e t any agent sh*!+ 'a""ant the *se ) the" a!te"nati1e agents an+H" $he(the"ape*ti$ "egi(en. The s*$$ess ) the $he(the"ape*ti$ "egi(en is *!ti(ate!y (eas*"e+ #y t' #se"1a#!e pa"a(ete"sB in$"ease+ s*"1i1a! an+ #:e$ti1e +e$"ease in t*(" si5e. The p"esen$e ) a 1e"y "e!ia#!e t*(" (a"3e" in GTN, hCG, 'hi$h $!se!y "e)!e$ts t*(" #*"+en, a!!'s +$*(entatin ) #:e$ti1e "espnse t t"eat(ent +*"ing the $*"se ) $he(the"apy. I(aging te$hni4*es (ay a!s #e *ti!i5e+ t assess "e+*$tin in t*(" si5e an+ +isappea"an$e ) !esins. C(p!ete "espnse is +e)ine+ as $(p!ete +isappea"an$e ) a!! (eas*"a#!e +isease )" at !east t' (eas*"e(ent pe"i+s sepa"ate+ #y )*" 'ee3s. F" gestatina! t"ph#!asti$ +iseases, $*"e (ay #e a$hie1e+ 'ith the *se ) $he(the"apy a!ne. S;MMARY The (ainstay ) t"eat(ent )" gestatina! t"ph#!asti$ +iseases is $he(the"apy. C*"e $an #e a$hie1e+ 'ith the *se ) this t"eat(ent (+a!ity a!ne. F" antinep!asti$ +"*gs t #e e))e$ti1e, se1e"a! )eat*"es (*st #e p"esent. These a"eB -. The +"*g (*st )i"st "ea$h the $an$e" $e!!. =. It sh*!+ #e p"esent in s*))i$ient t,i$ a(*nts an+ (*st "e(ain in the $e!! )" a p"!nge+ pe"i+ ) ti(e. >. The $an$e" $e!!s (*st #e sensiti1e t the e))e$t ) the +"*g <. An+, a!! these (*st $$*" #e)"e "esistan$e e(e"ges. The patient (*st a!s #e a#!e t 'ithstan+ the a+1e"se e))e$ts ) t"eat(ent an+ sh*!+ ha1e a p"pe"!y )*n$tining i((*ne syste(. The +se, +se intensity an+ s$he+*!e a"e i(p"tant 1a"ia#!es in the e))e$ti1e t"eat(ent ) the $an$e". It is 1ita! that the @)*!! +sesA #e gi1en @n s$he+*!eA )" a sh"t pe"i+ ) ti(e t e))e$t a $*"e. In $ases ) "esistan$e, a (*!ti (+a!ity app"a$h (*st #e $nsi+e"e+. REFERENCES -. S3ee!, RT %e+&. Han+#3 ) Can$e" Che(the"apy. Lippin$tt 6i!!ia(s an+ 6i!3ins, Ba!ti("e, =77>. =. Pe""y MC. The Che(the"apy S*"$e#3. Lippin$tt 6i!!ia(s an+ 6i!3ins, Ba!ti("e, =77G. >. Phi!ippine Natina! D"*g F"(*!a"y Essentia! D"*gs Mng"aph. F!. = 0 th e+itin.The Natina! D"*g C((ittee Phi!ippine Natina! D"*g P!i$y P"g"a( Depa"t(ent ) Hea!th. Mani!a, =770 <. L*"ain MR. T"eat(ent ) Metastati$ Gestatina! T"ph#!asti$ Nep!asia. (n Gestatina! T"ph#!asti$ Disease. E+ite+ #y B6 Han$$3, MM Se$3!, RS Be"3'it5 an+ LA C!e. She))ie!+, ;9, =77., pp >I.2>.I /. Cagayan, Ma. Stephanie Fay S an+ Ga$#a, C"esen$ia CB Che(the"apy Regi(ens ;se+ in the T"eat(ent ) Gestatina! T"ph#!asti$ Nep!asia at the Phi!ippine Gene"a! Hspita!B T"eat(ent O*t$(es an+ T,i$ity . J Reprod Med 2006N /-B .7I2.-G 0. S*ng HC, 6* PC, Yang HYB Ree1a!*atin ) /2)!*"*"a$i! as a sing!e the"ape*ti$ agent )" gestatina! t"ph#!asti$ nep!as(s. A( M O#stet Gyne$! -/7B .=<,-.G<. I. 6ng LC, Ch YC, Ma H9B ;se ) "a! FP-02=-> as p"i(a"y $he(the"ape*ti$ agent in t"eat(ent ) pst(!a" t"ph#!asti$ +isease. A( M O#stet Gyne$! -/7B .=<,-.G<. G. Ming O, L*an T, Sh*2Feng OB C!ini$a! Pha"(a$!gy ) Cy$!phspha(i+e an+ I)s)a(i+e. C*""ent D"*g The"apy I //2G<, =770.