I',." ,. 'I"C,' .. ,,/ I" ',~ Ii" , "I ("."".",...""" 1)./".[".,-. " 1,,,,1 b,
`
`
`
`
`
`
`
`
`
`l),:,el k"~ "' ",,,_ .~",,,J I Sd",. S'"WO A. 1_'11...-1. ,""j P.',I II
`
`
`
`
`
`
`
`
`1..,,,.,'_ L'I1f".:'~' R,,,·u. P"~h,I"'", 11"1.""I"h .. ,, I''',
`
`
`
`
`
`
`
`
`
`
`
`
`
`CH APTER !::\
`
`
`Principles of Chemotherapy for Genitourin ary
`
`
`
`
`
`
`
`Cancer
`
`r Il lplicatio ns fo r Deve lopme nt of New Anticancer Drugs
`
`
`
`
`
`
`
`
`
`
`
`
`
`b trick J. Creaven a lld Derek Raghavall
`
`
`
`
`
`
`
`
`
`
`
`
`{'\ l"w.~ic ~ hell1()[hc)'~py h~, /Jec n in "'" forth ... munagement of
`
`
`
`
`
`
`
`
`
`
`
`"I> .lIlo;~'1.l canet:r for more than a cenlury.1 arising from (o.wepts
`
`
`
`
`
`
`
`
`
`d"" c-Iop,xl by Li,sauer. Ehrlich. ,lIlei 'nany !lthers. Tht: initial
`
`
`
`
`
`
`
`
`
`.lltc'I1 IP!S <II sudl rreJtmcllI were churlc\crizcd by a lad of ~peci ­
`
`
`
`
`
`
`
`
`
`
`
`
`lie ily. wilh a line balalll'e hetwecn the to,;C;!)' 10 Ihe IUlno ra nd
`
`
`
`
`
`
`
`
`
`1i-.lI e \pefi~ IKcd hy Ihe hos!. As n:vicwcd in delail c l"" wh~ re. 1
`
`
`
`
`
`
`
`
`
`
`
`du ri ng the p~~l ccnl ury. our appli<"aliun of l' hemoth cr~py to the
`
`
`
`
`
`
`
`
`
`
`t,,'a Ullel,t o f c~nu.'r h;~~ been refin~u.l,rellic<lteu on ~II inlproved
`
`
`
`
`
`
`
`
`
`
`tlllder-landing of the bio(:hemical bmis of its uCTion :Ind a l'lc~rer
`
`
`
`
`
`
`
`
`il1' lgh t into the ce llul,lT ;tm! mole~u"'r ntelhan;_,ms "'l,lcdyillg
`
`
`
`
`Ih,nn,,! aud malignam gTllwth,
`
`
`
`
`
`
`
`rU MOR CELL IHOLO(;Y I N RELATiON TO
`
`
`' IIEM O T H E RA I'Y
`
`'Ill\': a"li~<l n~t"r agems are a varied collection nl' clrug_~ that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`"'t Ihrough "r:lnge of rnecha flisms. predominantly locu.-.:d on
`
`
`
`
`
`
`'''krferelll'c with cell reproduction. Inve,tiga!oTS gCllel';ltJy
`
`
`
`
`
`
`
`
`
`,'g ree tha t the difft"re lKcs betwcen ttr growth <'har~rteristi~s o(
`
`
`
`
`
`
`
`
`
`
`,,,"mal ~nd Ill<llignnnt ti~,ue~ form the major basis of the erlcc(cid:173)
`
`
`
`
`
`
`tl\ C 11M: of cytotoxic chelllothcrJPY.' Diffcl\"lKes :ullung ('dlu(cid:173)
`
`
`
`
`
`
`
`
`
`la r Iran'(Xlrt ch~rJrteri.'l i c ." with d ifferential upwkc ami odllta
`
`
`
`
`
`
`
`
`
`(\1' l'ylohnic :tgcnr~, may also contribute to the difference in
`
`
`
`
`
`
`
`
`r" ~p()tl~e to SOllte CytOIO,\i\: 3g~'nts, Moreover, illlpurt~rtt dirTer·
`
`
`
`
`
`
`
`~ l l<"es Jpp;trcntly ex ist amu"g intracellular Illdaholic t'lJnction~,
`
`
`
`
`
`
`
`
`
`, "th as the expression or g lut:lthione, an intr~cellul<lf scavlougcr.
`
`
`
`
`
`
`
`
`
`\\ hkh intcracts with -""ne "Ikylaliu(! agent.' alill Ihe phttinu!l1
`
`
`
`
`
`
`
`
`c'ulllpll'xe~ III inal,tivatl: them. Mo~ rel'ent datJ "uggl'sT the
`
`p •. " "ibility ,)f subtle imeradivns il<'lw<,cn the (O,\ prc,sion nl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`growlh -controlling factors, ,",'h a, tile r~l'eplllr for thc epider(cid:173)
`
`
`
`
`
`
`
`
`
`
`IIwl growth factor. ~I)d the impact of cytotnxic ;t!!cnt". wirh
`
`
`
`
`
`re ~lIlting ,yn<:rgi'ljc' or <Hltag"niSfil, elf<:l"1',
`
`
`
`
`
`
`
`Normal ti ,~"ues :Ire ,'Olllpt)-,<'d prcdomin:1111ly of a 'T~t ic P()PI!(cid:173)
`
`
`
`
`
`
`
`
`
`
`r.ll ion or ~'c'lb {h,,, nordy unJ~ ,'!:-" .:cli ,Iivi~i"", un <:xpu,ullI'g
`
`
`
`
`
`
`
`
`
`
`
`
`IJOpulalion of l'cHs thaI rctainlhe ~b i li ly to grow, under striogellt
`
`
`
`
`
`
`physiologic conTrol mechnnisms, afld a sdf~renewi n g ptlpula(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`lion for tissues that turn over rapidly, "u,'h ~s bonc lIl~rruw allli
`gasTruintestinnl epithelium, In this situmi()!1, balam:e i~ main(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`tained betwecn naturJI unrition and rcpl:ll'emen1.
`
`
`
`
`
`
`
`l1w st:tlic , ur t",rmin~lIy diffcrentiated, pop ulatiun usu~lly
`
`
`
`
`
`
`
`
`
`
`
`il1c1ude~ cells that do nOi undcrgo cell div ision after fetJI life,
`
`
`
`
`
`
`
`
`
`
`
`such a" ,kdclal "tusek anll neuron~1 ti~~ue. The cells of an
`
`
`
`
`
`
`
`expanding populatioll do no t normally undergo continuous
`
`
`
`
`
`
`
`
`
`
`growth and divj,iol1, t ut they may n:-~polld to ,'Ire'~, ~lIch a,
`
`
`
`
`
`
`
`
`
`
`injury, wilh a pt'riod of rcpbccmcnt growth, Forexnmple, hCPJ(cid:173)
`
`
`
`
`
`
`
`
`
`
`h:x:yteS cart respond to '1lr£ic:l1 re,,--"Ction uf liver tis,ue by reen(cid:173)
`
`
`
`
`
`
`
`
`
`
`tering the cell cycle unJ rcpl~dng the lost li,sue, Another e.,~m ­
`
`
`
`
`
`
`
`
`
`
`
`
`I'll" of !he e ~ pall Jing f.opulation i~ the st<:m cells in till" bone
`
`
`
`
`
`
`
`
`
`
`
`
`ll1arrow: these cells norm~lIy rest in the G" ph~sl". bulthey can
`
`
`
`
`
`
`
`
`
`
`
`reenler the cell cycle, Th;>t the y an:: I'rcdomin,,,uJy in G" may
`
`
`
`
`
`
`
`
`
`
`proteCT !hem. in pan, from Ihe eirects uf cytoto~il' :lgents.
`
`
`
`
`
`
`
`
`
`
`By wntra~t. the ~If-renewing cell popuhlliuns, ~u" h as cells
`
`
`
`
`
`
`
`
`
`
`of the ga"tro inte~ti l1al1racl, hair lollicles, alld bone Ilt~rrow, arc
`
`
`
`
`
`
`
`
`in a continuous proli Ji:rative slate, with c()n_~lJn t cell tunlover.
`
`
`
`
`
`
`
`
`~Ild itrc Thu_~ mmt eom,n()nly injured by cytot(l.\k l'hcmOlhcr(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`apy: the ,Italic cell populat ions are th e least \"ulner<lbk to the
`
`
`
`cffcl"l,' of chemnther:lpy
`
`
`
`
`
`
`
`
`,\h ligmml grow th i., essentiall y II nl'Ontrollcd, occulTing ~.' a
`
`
`
`
`
`
`
`
`
`
`resull o f a breakduwn in Ihe rTll"chan bms th~t IlIrn off growlh
`
`
`
`
`
`
`
`
`
`
`The pal1ems Ihat contribute to tum()l" growTh m;ty inc lude a
`
`
`
`
`
`
`
`
`
`
`
`
`
`reduction in the length of ihe cell cycle, II decrease in the rate
`
`
`
`
`
`
`
`
`
`
`
`
`oJ cell dCilth. or ,to jn~rea ,e in rc.:;rui tntt"nt of cclL\ inlo the
`
`
`
`
`
`
`
`
`
`
`active cell cycle_ In ge n~r:JI, m;tlign:ml growth appe~n; to follow
`a G()l1lpo.'rtz i ~n putlcm.1 in whkh a period of e~IXJllenti:J1 growth
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`is ro llowed by a ,lowing of the grov.'th rale, This process muy
`(I(:.-ur through the tumor's outgrowing it, viI.,cubr ~upply, as a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`result of Ihe <.i<-vcJ npml'flt oiToxic brc;lkdown products associ·
`
`
`
`
`
`
`
`
`
`ated with ,'ellular turnover, or through orllO:r subtle l'cI /- celt
`
`ill!<:r;,~! i"n,
`
`H9
`
`
`NOVARTIS EXHIBIT 2056
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 22
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Th,' killeti,', of tumor cdl gn"oI'lh, hOlh in vil ro <.lnd in \' iv(l.
`h"x I:...-,'n Ih,' , uh je('l of ( ",,,ide r~blc' , 1U,'Y.' "hh""gll "",. ("on(cid:173)
`
`
`
`
`
`
`
`
`
`('t"pts un lhi , lop ic rt.'lllain Iluid, Su .. pri'ingly linl!' infoflll:lr i.1Il
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`i, ava il"bk rel!'lIlling tht' kitK'lk~ of hum,tn !lImn .. W(lwlh. '
`although a grt:ater body ur ini"oTllta ri utl i, ,t v,til"hk <lIt the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`growl h of an inlUl lumo rs.1 r nvt~ti g ators gener,tlly agrec Ih:,1
`rUlllO], celb !,'!'IlW thwltgh ~ Il onkrly se4ucltt'e (>1' slel's
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`I. 1"IH: in il i,tll,'fu wlh pltasc (G t) i, ('haracl~riz("d by symhcsi '
`
`
`
`
`
`
`
`
`
`of ri bonllcleic: acid ( RNA) ~nJ pro ldt). a" w<'ll as deoxyri(cid:173)
`
`
`
`
`
`
`
`
`
`
`bo nude i,' ,Kid ( DNA) rqmir: tilL, i, ,t [l<'riod o r variable
`lell!;!th. mI(l it., dU r<lIion del~n ll i lles Ih" lell!;!lh of th e t01,tI
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`~ell (,yele or the individual (ell.
`2. Thi~ ph".,..- i~ folluwed by Ill.: ' ynth"-li(" (S) p)w ~. ill wh id )
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`new DNA i" synlhesiz,'d.
`
`
`
`
`
`
`
`
`
`
`
`
`~, The cells p'\,!;!rc" Ihrough Iht' G ~ pha,t:. ill whi,·1t Ihe wtal
`
`
`
`
`
`
`
`
`
`DNA c()Iltent is duublc Ihm or Ih..- n0 fl1H11 cdL
`
`
`
`
`
`
`
`
`
`
`4, The milO(ic ( M ) pitase set:, Ihe divj,iUll of Ih,' d l rol1lo(cid:173)
`
`
`
`
`
`
`
`'omes and se paralion into tWO o ffspring (ell,
`
`5. After lllilOsis, th e cell., may spcnd a variable pe riod in :1
`
`
`
`
`
`
`
`
`
`
`
`fe,ting Mate kno ..... n as G o: t,1(: (",lis "n: OUI of uCli,'c cycle
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and appcuf not to be ~rfl''(:lcd by (bemO!herapy!ll Jny majol
`
`
`t"'Xll'll1
`
`
`
`
`
`
`
`
`
`
`
`A detailed descriplion of Ihc rnolet:ular biology of cell <:yclt:
`
`
`
`
`
`
`
`
`
`
`
`conlro l i, beyond lhe sco pe of Ihis chap1l'r, and Ihe princi ples
`
`
`
`
`
`
`
`
`
`are rev iewed ehewhere,4 In brid. se veral (a ndidJte ge ncs and
`
`
`
`
`
`
`
`
`
`
`
`growt h fat'IOr, uppcar III regu late Ihe various .• Ieps o f the cell
`cycle, For exalllpk. in di fferent tis, ur ~, e nt ry into G, ~PPCMS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to be tl'!!uialed by a rang!: oj' fallll". inciud inJ:! M)'C ,lIld FOS
`
`
`
`
`
`
`
`
`
`(fortne rl y kl)own ,IS l'-lIlrc and ({o,,' ). platelet·derived l,!rowlh
`
`
`
`
`
`
`
`
`
`fac t or~. Jnd i n,ulin - li~e growth fa-.-Io r-I ami it, ren'pl""
`
`
`
`
`
`
`
`
`
`A lllajor <:ell ,'ycJc cOn!rolkc p~4" 'k~ . IT'l,!u lmt's cnlry ill1(J
`
`
`
`
`
`
`
`
`
`
`5 ph<.l,e: thi s protein llppcurs 10 b,1\'e b<."C n con.'eTvcd during
`
`
`
`
`
`
`
`
`
`
`eVI!lution from yea~ts 10 hu mlulS. with rega rd Hllx'lh structure
`
`
`
`
`
`
`
`
`
`
`
`lind fu nct ion.' In turn. Ih is kin,h e <lppcar.~ 10 inlCra(1 wilh il>
`
`
`
`
`
`
`
`
`
`
`l~rJ;ch by a'Mx:iation with thc (ytlin.,. a fumi ly of pu~ e in.,
`
`
`
`
`
`
`
`
`
`
`
`
`fou nd in different ,tages of I h~ cdl cycJ ~. T be G, (ydin' " re
`
`
`
`
`
`
`
`
`
`
`
`
`p re,c nr befurt, 5 ph ase. and lhey intl"r<.lc i wilh r)~4 to ( ause thl"
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(dis 10 entcr S phase. Entry into 5 phasc is Ihe fi n" m ajo r {'ell
`
`
`
`
`
`
`
`
`
`cydc conlro l poinl. Thcs<' cyei;"" "prcur h' inlem<: t directly
`
`
`
`
`
`
`
`",' ith OIl1:llJ;C IK'S "od wPJlrcs~()r grncs. r flJOahl y Iltrllugh" rhll~ '
`
`
`
`
`
`
`phorylarion functioll of the eyciin-pJ4 l'(Hnpk.,.
`Seven,1 (HlCoJ;e llc, . . ,uch a\ HAS a rid SHe (formerly knuwll
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a' m .I' and .\'/"(' 1. have ul·tivit y in Ihc M pha'c of Ihe l'eJl{'yc!e:
`
`
`
`
`
`
`
`
`
`
`
`
`in );Il l. Ihey may a-.-tuall y il11CrKI ill Ihe pmee" leadi ng 10
`
`
`
`
`
`
`
`
`
`al'tiva tioll of Ihe M- ph".\e prol)luling f"c lor. whidt. in tu rn. C\Ht(cid:173)
`
`
`
`
`
`
`
`
`
`
`IflJi.- cnll y into milOsi.' nhe .~cmnd major (ell cyclc control
`point). Tumor prugr<:ssiufl ma y be a IU,1('tiOIl ()I' " M:rie~ or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cvcn!.s involving progressive h,s, .. fuml",1 "vcr elliry inlu lhe
`
`
`
`
`
`
`
`
`
`
`
`S [l ha't' ,lIId I"" nl' rqml:u i()11 or M ph:l'<': ,udi pf\'g rc , .. ion
`
`
`
`
`
`
`
`
`
`
`
`
`i, due 10 g"lIetic' ill'lahilily und i.' l'e 'tl ra l I" Ihe cvol ulion of
`
`
`
`
`
`
`
`
`
`
`1I11,ligllallcy, Th",e l'h'tIl!;!<',' liMy h,' O)IH in)1<'llt (In the los~ 0)
`
`
`
`
`
`
`
`
`
`chcdpoint fl,neli,,'1. a otct'h"ni'lll hy which Ihe eel! ,-yri<:
`
`
`
`
`
`
`
`
`
`p;11I.' CS lr'lIl,ienr ly and "lIow.' dl ec kin g of the al'l' uroKY of I'l"pli"
`
`calion."
`The l"tlli(."cpl of (1)( ceJl cyd c i., fir g''l"al impon'llt,·c 10 our
`
`
`
`
`
`
`
`
`
`
`
`
`1I'ld<' r' I ,llId l l t~ "f cylor<l,\i(' "('l i"ll. ~'I'''I ~~cnh alTrct ,<'m<, :I,.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`l)Cl'l oflhe ~YIHh(',i, ()f DNA. RNA. or pmlt'in and ;(l"t at d irler-
`
`
`
`
`
`
`
`
`
`
`
`elll poilll .' w;111I1I Ihe leli I: ydc, T hi, filld ill!! Ill"), I)C IInport" m
`
`
`
`
`
`
`
`
`
`
`when adlli ng "gellts ill " "ornbin:tl ion rcgi m en: fur cxum p le.
`
`
`
`
`
`
`
`
`
`
`
`the usc o f" .'pindk IXliso)] (suc h ,tS" vinl'it a lbloidl tllu\, hold
`up t't' lI, j'rn'll Clll!) illl" Ihc 0 , I'lwse <llId lit" , Ittay rcdll~'c thc
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`imp,1{"1 of all " gem Iha l ,1('1.< prt'dom inantly at lltat poim of Iht"
`
`
`
`
`
`
`
`
`
`
`
`
`cell cyt·l.:. Tlli, dfcl'l i~ limiled by the IIlIdinJ; IIl;ll rt\,II'Y agt:ll1s
`
`
`
`
`
`
`
`
`
`
`
`,1<"1 al mullipic [l<,ints in Ihe (('II cyde. Inbibiti()[] of cht-c kpo int
`
`
`
`
`
`
`
`
`
`
`
`
`function Ill;!)' ex pbin the ..... ay in whit'h IUlllor cd l, can be mort"
`
`
`
`
`
`
`
`
`
`Vtl hl<:l~lble h ' rhc dfed" I))" ~yl(lw~il' "J;cnl, thall arc norma!
`
`
`
`
`
`
`
`
`
`
`
`
`cells: 11m" . the vil/rctabi!ily of <::ttl,'er ct'lI, to <t gt'IlI" Ih,ll targc t
`the S pha.,~ or Ibc M )l h" ,~ nt~ y t)(c ur Ilc('HUSC thc malignanl
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`cells prol:ced lIudt~ded Ihrull!;!1t !l1(' cell q'de de,'pit" " st'rics
`
`
`
`
`
`
`
`
`
`
`of e rro rs , whnea, Ihe norm al (cll- .'lOp ,][ finite checkpoinls
`
`
`
`
`while necded r~p"irs t)((UI
`
`
`
`
`
`
`
`
`
`Cell cyde eiwractcrisril'S l'HO he mc,l.,uf(,d i,\ sever,,1 ways,
`
`
`
`
`
`
`
`
`
`
`ind uding Iht' u,..- \'I' la beling o f milo.,<s1 and !low cYl<l metry.
`
`
`
`
`
`
`
`
`
`
`When mnsi dering. thc b io l o~y oflUlllor gr(lwlh as a"es~t'd oy
`
`
`
`
`
`
`
`
`
`
`
`!lnw '·ytUlllctry . (h~ rroporlio fl of cdb in th e G I lInd S phast"
`
`
`
`
`
`
`
`
`
`
`
`
`i., Iholl,l!ht to be mml importan l. althou gh thc It:vcl of allt'up loidy
`
`
`
`
`
`
`
`
`
`
`
`
`(prU/XliliOIi of "ell, Ih" t do nOI have J nUl'lll,,1 or di ploid DN A
`
`
`
`
`
`
`
`
`
`l'OIltCnl) upf'C,ars 10 Ix; lltl illtponanl jlrog,loslic dClcnlli na lH i'l
`
`
`
`
`
`
`
`
`
`
`sOllie tuntor" Anolh er. m()f~, direc t par"mell'r of the cell cyclc
`
`
`
`
`
`
`is Ilw ,l.\urelllCIH of tUlllor tloubl ing lime .'
`
`
`
`
`
`
`
`
`
`
`Abo of importilocc i~ til.; growth f .. "ction (pr<>p<lr1ion "f edl ,
`wi thin J lumo r Ihal ~rt, itt a(live proliferalivc phasc) . ..... hi(h GltI
`
`
`
`
`
`
`
`
`
`
`rnngc from ~5% to nver 'KI't< , in hUllllln tumor". The r~tc of cell
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IlN' is '11.<0 importllnt: in 1110,1 IUlI}ors. il is hi J!h. ranging from
`7U'1r 1(1 ovcr 'X.J%.~ In gcnerJI. lite I~nglh of~th~ G , plmsc is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`one urlhe primary ,Icte nn in'l nl." of prolifermive bdl<tvior: lit u"
`if G, is short, thc ~uralion of th e ceil cydc is u., uaily rapid.
`
`
`
`
`
`
`
`
`
`
`
`
`
`whereas cell" will l'l iollg G, or thme Ih'l t spend c()n~jderab l t'
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`rime in G" have a much lo n.!!~ r ,'ell ('ydc alltl arc Ie~s sensitive
`
`
`
`
`
`iI) Ihl' iml'urt of t' htmothe filpy,
`
`
`
`
`
`
`C!onalit.r IIf Tumor Cell Pupulal ions
`
`
`
`
`
`
`
`
`
`
`In an im:ll llJmors , whi,,1t tend I" be (lon;!l, first-ordcr kinelic,
`
`
`
`
`
`
`
`
`
`
`
`
`arrears to "pri y in rcspon,c to chcll1ol h~rapy: "wr is. :l dose
`
`
`
`
`
`
`
`
`
`o f , ingle-agcnt dle motherapy kil l, a 1I.\ eu proponion of tumot
`
`('e ll,. For examp le. if a IUllIor ttl:!sS containing )()7 ,'db i ~
`
`
`
`
`
`
`
`
`
`
`tre ,Hed wilh all agent th<l l kill s 9()'k of th e cell~ . 9 X Ill" ("<.:11,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`will be killed by ~ .Iingle do,e . Ica vin!:, Ixh iml 10" vi<.lbk rc )J,
`(or IO'!t, of 'he ori!!in"! tUllIor Ill""). A '1:(01,,1 01,,,,,, kill , 9 x
`
`
`
`
`
`
`
`
`
`
`
`
`
`10' ('cll, and Ie,,\~e, 10' ,'c lls sl ill alivc. If Irelilment is not
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`repealed , these ,'elb will reg r"" ·. anll Ihe nw, ~ will rapidly
`
`
`
`
`
`
`
`
`
`
`
`relurn In its fonn~r size. Th i, proccss is al'l' influ~"n:il by the
`proportion of (clls that undergo s[Xlllt,meou, ,'ell demh. as well
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`II.' the prolif('r,ni vc "lie of <.I ny rcnta ininJ; viable cclls.
`
`
`
`
`
`
`
`
`Clill ieaJl y, Ihe , Iu"tion i, Illudt mort.' t'omplex . becau ~ e
`many ltutTIan tunwrs ,tpJ1C;t r nOI In he purely un iclonaJ. but
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`rmbcr an.' u llnpo:'seJ \If m ullip le ,uhpn pu lali"Il" or eelh with
`
`
`
`
`
`
`
`
`different dHlI"~l'teri;til·., .7 W hdlter thi, phl'1I0I n~[lOll i, dil l" I"
`
`
`
`
`
`
`
`
`
`
`I h~ el"\llutioll (''''Ill ' in!;!lc d Oll,d populations (S I ~11I cell,) <lr i.,
`
`
`
`
`
`
`
`
`
`
`
`GII',c.1 hy in itia l ~v "llll ioll " I' ll'u h ipk d " lie' III rC ' lxllt'C III a ll
`iniliJI ";tr,'in"genic 'Iilllll l", i, nUl dear
`
`
`
`
`
`
`
`
`
`
`
`PHAI{M ,\UII'(H;Y Of ANTICA NCER A(;ENTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`The timc ('nUI"" of Ih e "".inurn of .Iru!;!, in the !xxly i., Iit-Ief'
`
`
`
`
`
`
`
`
`
`milled hy IIt~ r!!IC, (~ ' drul:' al"N,rpl illn. di'lribl'li"ll. nlclatx,l i'lIl .
`
`
`
`
`
`
`
`
`,ifill (,WfCtion. Thc mal helllmi<" dc.;nipti".l <I[' 11K'\(' ralC pw-
`
`NOVARTIS EXHIBIT 2056
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 22
`
`

`

`I' ~I:-'I, I I'IE:-"J~ ( : 'I ~"' ( >lIIH.:.II·\ ,-1 1K ( ;,:\11111 KI,IKyC\\ • .H1: J 9 1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`c' ~ '''~' j, rdcnc,1 to ~.' pharm<l<:"J". illclio.:s. Of!<:o. the dM;! call
`
`
`
`
`
`
`
`
`
`I..., fined to I1wli U:lllal il Illodd, tl Ml arc ,implilktl dt.'nir'i"'l~
`
`
`
`
`
`
`
`
`
`" f the .:ompiex rlly~ i<ll"l!i(; n:a'ili.: .• _ Many of rhl'S<) pnlol'c',,"-"
`
`
`
`
`
`
`
`
`
`
`
`
`..... : sO-l"alled tirst o(dn: rl tar I', rhe rUle <11 which lh~ pro<.,.;"
`
`
`
`
`
`
`
`
`
`, ,,Tu rs is propurrional 10 r'w lIrug: c-'"lo.:culruri(l n. alr hough ,om.:
`
`
`
`
`
`
`
`
`l'rocc-"sc,' Ihat depend 01' cm:ymc." or carriers follow '''l icha~li.' ­
`\ [cnlc.] kin<'lics. in wh id] the pr .. :,:<.'-", i, fi rst oIT!..:r a' low COIl(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`,'clll rarjons ;uuJ zero order I i.,-'. , occurring :II a fi.\ cd ralc) :" high
`
`
`
`
`c<!necm r;uiolls "f the drllg .
`
`
`\hsorption
`
`
`
`
`
`
`
`
`
`crto[o)(ic agcllIs m:ly bt: ~dm t n i s!ercd .lireuJy illlo Ihe dn:u(cid:173)
`
`
`
`
`
`
`
`
`
`i,I!!n" {intravenous or inlr;l~ncr i al admini\tmtion) or by the c,(cid:173)
`
`
`
`
`
`
`Ir"v'lscui;Jr :.ppro ac h. ""hich in:ludcs nr.li. inlrJ ll1 u~cul"r. in(cid:173)
`
`
`
`
`
`
`
`
`Ir"thecJi. inlrJvcsic.1i. und im rupt'rih>ncul roUles, The fIlme o f
`
`
`
`
`
`
`"\!r1lv'l,;culardel ivery intJut"llce' :,hso rpTinn. F"c tor~ lhal deTer(cid:173)
`
`
`
`
`
`
`
`
`
`Jl linc The upluke c haracTeristics of 11 <1m,!! indude Ihe ,trunure
`
`
`
`
`
`
`
`
`
`
`
`Cl UJ size of the molecule and i t ~ fleJ;u li vc lo!( of dissoci'llion
`
`
`
`
`
`
`
`.. <,n,tant (p K'I ) and. thu s. iTS ", .. ubility L· b:!raC!eri~Tjcs.
`
`
`
`
`
`
`
`
`
`
`The clinical aC TivilY of IJX:C·/iC 1gents m~y vary wi th Ihe
`
`
`
`
`
`
`
`
`
`""nor" nf Ihe muTe ami s~hedu li." of ;ulminist ration :!fld conS(O(cid:173)
`
`
`
`
`
`
`
`q llent absorp ti on. For example. cycJophosph:!m idc can be ad(cid:173)
`m inistered orally in a do . ..e of 100 mg/m!ld for 14 days to pa(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(ienl' wi th advanced pros tafe cance r ami i.~ wdl In/crJled.
`
`
`
`
`
`
`caus ing only m()(]esl myeJo"uppre% ion and gastrointestinal 10X(cid:173)
`
`
`
`
`
`
`
`
`
`
`ici ty ." WI1<'n Ihe drug is adrllini,tl're,1 to , imilar populalions of
`
`
`
`
`
`
`
`
`
`
`J'a ticms by in tr.lvenoos bolus injcction (e.g .. 750 to 100CJ rny
`
`
`
`
`
`
`
`
`
`
`
`Ill! t:"e ry 3 wet:b ). the side .:ffecls may be more su bstam iai."
`
`
`
`
`
`
`
`wilh no app;lren l improvemem In IhernJX:utic o utcome
`
`
`
`
`
`
`Succe.",~ful intravesical chemolhua py is prediCJTed on Ihe
`
`
`
`
`
`
`
`
`
`
`
`d ~sire rur cywloxi c agcnts 10 be a"l ivt: locnlly wi/luJilf !iy~ lt:fflil:
`
`
`
`
`
`
`
`
`. Lb~orpliOll, thu s protecting the pat ient from sy.ltcm ic side cf(cid:173)
`
`
`
`
`
`
`
`
`
`!'ecls wh ile maxi m izing IIII' l'olKcnt rat ioll ,II Iht: llunor slllf~ee .
`
`
`
`
`
`
`
`
`rh us, Ihiolep~. a sm:.lI . readil y abso rocd molecule. is potemially
`k,., u.leful in lhi. e()nle~t Th~n largt:r mokcule, .• uch as do xoru·
`
`
`
`
`
`
`
`
`
`
`hicin or mitomycin C I" FUr!hemlOre. the level of syslc mic ah(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`,orption of thiolepa can be inc n:ll~ed if Ihe age nt is :Idministercd
`
`
`
`
`
`
`
`
`
`
`,oon aflel' lransurethral tumor resection in thc pl'esencc o f a
`
`
`
`
`'\'sidual den uded bbdder epilhelium.
`
`
`
`
`
`
`
`
`Ulti m ate ly_ the key (0 Therapeutic effenivene's of any cylO(cid:173)
`HlX ie' a~cm i .~ a functi on of the product of its concentmlion ;Ind
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the li me av ai lable al the uUlIor ,ite (C X T). MO,I cytoToxic
`
`
`
`
`
`
`
`
`agents are admini ste red by intravenous or iru rJarterial routcs.
`"ud calculaTions ,If lhe ,letual pl ~sma C x t equal ion are made
`
`
`
`
`
`
`
`
`
`
`
`
`:lccordi ngly.
`
`
`
`
`
`
`
`
`
`
`
`,h"w~ 1"'0 <''''''ponems "f Ihe p l a~lTla <kcay: an inilial r~pid
`
`
`
`
`
`
`
`
`l'orllrollenl ;lIId;1 "ul>'C4uClll ,'own cOlllponent. hUI" "f ""hi~' h
`
`
`
`
`
`
`
`
`have Ihe ehar;lclt:li'lil:s of 1()!,!-lille;IL thaI i •. Ii r' l-order. pro(cid:173)
`
`
`
`
`
`
`
`
`
`
`"cs,c.'. Mathelllal ic~lIy. ,ueh ,I ph,m:! d~l'ay ";111 be ti tte,1 to a
`
`
`
`
`
`
`
`
`1"'",cH"'par!!nenl "'0I1e1 if! which Ihl' hoJy is cunceptu'II izcd
`
`
`
`
`
`
`
`
`a, l'on, j,ting of 1\\1) enlllp~ rllncn t s. a ('e lU ra l CoH1p;H1mem inl o
`
`
`
`
`
`
`
`
`
`whi<'h Ihe dru~ i, introxlueed ~nd a ~ rirhe ra l "r lis'lle n,mparl '
`
`
`
`
`
`
`
`
`Ine'IT into wllkh il di ffu,t:s. ul!imaldy t<1 equilibriuIll, The .,ec·
`
`
`
`
`
`
`
`
`
`
`ond o ' rnrx )llcn t "I' thl: plaMl'" dec:Jy e nnsi,,!> of Ihl' clirninalio(l
`
`
`
`
`
`
`
`
`
`
`processcs .. r lllt:tabnlisrn or ex vL'Jinn. The r., te 01' th is ~e~:nlld
`
`
`
`
`
`
`
`
`
`
`
`
`
`pro,:ess gives Ihe half· life of the drug iu Ihe body ~nd is an
`
`j"'portant ph;mnamkim;ti c Lll;":U:lerislic of "I I drugs (!~fh Fnr
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'Olne drugs ~uch ~~ the anlhraqdines, a Ihird compllrll'1ll 01
`
`
`
`
`
`
`
`
`
`Ihe pl:ISlllU decay j) seen irxJ;"alillg ~ so-taIled dcep ti~"ue com(cid:173)
`
`
`
`
`
`
`
`
`
`
`parTInt:nl usually lorre.~rond i ng 10 The binding of Ihe drug to
`
`
`
`
`
`
`
`
`
`
`some lissuc ,'o'nprllll'lll suc h as nucleic aci d from w hi ch Ihc
`
`
`
`
`
`
`
`
`
`
`
`"rug is ,lowly relea.'ed. An even ,i mplcr ,mxJeI in which the
`Ixxl)' h reg:~rded as a si ngle COIl1/XlrUllelll ('an sometimes be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`used. bU I for nmny ,1rugs iT call lead to major errors in cOlll puli ng
`
`
`
`
`
`rhe important phnnn:!toidnetie parameters. These "COIl! JXlft(cid:173)
`",ems" arc malhemati<; COUS lfllCTS thnT usuall y have lillie o r
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`nn cnrrespondenl't: with ,I('tual physi"logic ~·I)lnrarl llle rll '. The
`10lal area under rile plasma concelllratjon x lime curvc I f\VC
`
`
`
`
`
`
`
`
`
`
`or C x I) is ;"] impol1anl mNsurt: of the lotal e~ po_'ure of lhe
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`li.~.'ues 10 the drug. Olher impol1alll pham lacok ineTic par.ullelt: rs
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ihat can be calc ulated from The indices of plnsma decay arc the
`
`
`
`
`
`
`
`
`
`10[,11 body c le;lran,e ~ nd the ap/Xl rt'll1 volumc of distribul ion.
`
`
`
`
`
`
`
`
`
`
`the theore lic volurr,e rt'4uired lodissolve lhe !Otal bodYl'olllem
`
`
`
`
`
`
`
`
`
`
`"f Ihe drug if ir were unifonnly distrihu ted in Ihe concen tralion
`
`
`
`fou nd in p las m a.
`
`
`
`
`
`
`
`
`In gcneral. the d ru g is dislribmcd in imrJvns,'ul;lf, ext racell u(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`la r. a mi illl racelluilr waler. bU I il mus t cross ~ membrane TO
`
`
`
`
`
`
`
`
`
`
`
`pas, from one of these localions to another. [n addiTion. l'er!~in
`
`
`
`
`
`
`
`
`
`
`siles are prOleCleJ from ensy drug acees_~. Such saocl uari es arc
`
`
`
`
`
`
`
`
`u,u all y ch~rJc{erized hy lower drug con"ernr.lliun lhan ot he r
`
`TIS ~ ues
`The prt:.,ellce or sancluary ,;1".' "':!y be vI' real importmce:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`for example. Ihe bl ,~ od - brJin b".,.icr appe,lrs 10 prolel:! lht: hr.lin
`
`
`
`
`
`
`
`
`
`
`
`agu inst the local upw ke or cytotoxic agems. and Ihus the o"lin
`
`
`
`
`
`
`
`
`
`
`
`
`may he Ihe sill' "f rim rebpse in tum ors otherwise responsivc to
`
`
`
`
`
`
`
`"hemolherapy. Silllilarly. lhe teslis appu renlly may fUll(: liomll ly
`
`
`
`
`
`
`
`
`
`consti t"Te a s;mct,ury -,il" aga inST rht: effccT "f eh""'OIhc rJr>Y;
`Up to a Ihird o f pafients lre.,I .. '<i for mew., talic teMi, callcc r before
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`su rg ical rcnl<lvnl of Ihe affecled Tesl is have rc.,idual ca ncer
`
`
`
`
`
`
`
`
`wilhin [he Test is a l .lu!),;equen t orc hiec[olllY. despile all eXl r~tcs­
`
`
`
`titular ,'mn llieIC re.'pr.on,e.
`
`iJislribution llnd Tr:lIlsport
`
`
`
`
`
`M ela bulis lIl
`
`
`
`
`
`
`
`
`
`
`The nmoun[ o f cYIOIO.\ic agee t available nl the lu mor la rg"1
`
`
`
`
`
`
`
`
`
`
`
`
`
`.lIld lh~ length of lime during wh jch it i, present dctcrlni nc it~
`
`
`
`
`
`
`
`
`
`level of efficacy. SeverJI f~lclorl :Ire influcnti:ll. including Ihe
`
`
`
`
`
`
`
`
`
`
`
`lipid solubiliTy of the dru/!. its hind ing 10 prOlein and otht:r
`
`
`
`
`
`
`
`
`
`l'arriers. and the mechanisms avail,,!:>le 10 allow entry imn the
`
`
`
`
`
`
`
`
`
`
`
`lumor ("lCh as P:lss;ve diffusion or ;KTiw transport). A major
`
`
`
`
`
`
`
`
`
`
`
`radnr i~ Ihe pl:t';ITl~ levt:1 of Ille dlllg. major delenn inam.' of
`
`
`
`
`
`
`
`which art' il~ di ,tril>uliun 1.'h;lracterist ics. After r;lpid inlrave(cid:173)
`
`
`
`
`
`
`
`
`
`n()ll~ injel'linn. Ihe pia_sma cun';~rHr~li on of Ihe drug iniTially
`
`
`
`
`
`
`
`
`
`
`
`
`lilll> rapidly, In lime. th,' raIC o f decline "cereuses. A plot of
`
`
`
`
`
`
`
`
`
`tht: nalur.lliogaril hrn (1,,1 "l'"in,t lim,> /w",il,,1.' plm) g".,,, r;,lI y
`
`L
`
`
`
`
`
`
`
`
`
`
`Two imroTlant types of rnel~lxllism of anlitumor a/!enls are
`
`
`
`
`
`
`
`
`know,, _ Anlit Ulllor ~gt:ms Ih;lt rc.'emble nunn:!1 melaboliles arc
`
`
`
`
`
`
`
`
`
`O(len me labolized by the same mech;lnisrns as thc nonn" l me (cid:173)
`
`
`
`
`
`
`
`taholi te.'. Most purine <lnd pyrimidine anl imetabolile~ require
`JC!iv~l i un w a nudtlK ide. u,ually Ihe triphosphate. to he au ive.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`an d The'e reac ti ons arc ,'arri('d out by Ihe mechanism.~ in lhe
`
`
`
`
`
`
`
`
`c'dl u s~'(1 !O md~I~ )li l.e the corresJlOmling llulllWI prefurm ed
`
`
`
`
`
`
`
`
`purillCs ,In<l py rim idines ((he <;o--called salvage pathw'ly~). S(lrne
`
`
`
`
`
`
`
`
`of th e ;lIHjfolate~ uroder/!o pnIYJ;l ut,lIl):lt inn hy the r"echa n islll_~
`
`
`
`
`
`
`
`
`
`
`1l,,,(1 /,)r rOI:l1eS , Degr.ldalive r;UhW;lYS are '11'0 ac live in lhe
`
`
`
`
`
`
`
`
`cel i. sti ch as those respo llsihle for reducing: 5-nuorouradl t."i(cid:173)
`
`
`
`
`
`
`Fl I\ 1<. Llihy" n, . ,\ _ fll,,)"'''r,,~ i l "nd e,mvt:rl ,ng <'y""in<' "" ,"ino-
`
`NOVARTIS EXHIBIT 2056
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 22
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`,i,k 10 Ih~ ~"nc~I~II" li I)O: ur, ... il ,n"I>il)",i,k h) ,k,lII)il)" li" ...
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tlics" r<:~"tj'>Il' oc"ur III lilc ccll~ uf Ih" tum"r and in till' <TIL, of
`
`
`
`
`
`
`
`
`
`mmn"llis'1I1". In :.,hlilio" tu the>c 'f1<!6fil' Il1claM .. li~ o:,,(liol".
`<.'Olllj)('llilds tbetl ,It, not ,holl' rC"'l11hlml<'" 10 ph y,i"I,,)!i(' slIh(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`,t r<H t:' :uc m~tahn!i/.ed primarily in thc liva hy th~ palhw<lY'
`
`used fur d~{(I~ilj~ali(l11 "f ~elH.bimi~'. M"'I ill1port'"11 i, n~ida ­
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lion. of len followcd by wnju~illhlll. O~idali(ln i, carric,1 ""I
`
`by cylo('hruille P4.~(). a familv of clI/.ymes 1,l<:atcd primarily in
`
`
`
`
`
`
`
`
`
`Ihc Il1 icro~o1l1,, 1 ,'f 'Illoolh cndor la'lllil' relicululll frolclion of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the li ver. This pathway i ~ non'rccifi~ ill t~rlll' or ,tTUClur,tJ
`
`
`
`
`
`
`
`rcquircnll'Ol' and oxid iles 1ll0~1 Ijpid·soluhle contJ}Ound.,. This
`
`
`
`
`
`
`
`
`pathway i, r~,pon,iblc for th~ ini!i,,1 nxidatinn of the oX<lzilpho·
`
`
`
`
`
`
`
`' plwrine rill~ of the "xaZ!lpho,'phoril1", t:ydophu,pll,"nidc '"Id
`
`
`
`
`
`
`
`
`
`ifo,fillllidc, a reac tiorl leadin~ IOlhe conver,ion of thesc nnll(cid:173)
`
`
`
`
`IX'UI1(b to thei r active lIlelabolite,.
`
`
`
`
`
`
`
`
`
`K llowkd~<, of rllC IIlClilbolisl11 of cylOlOXi<, agcnt, i~ imj'<lr·
`
`
`
`
`
`
`
`
`tal1l in d""i~llin!; Ilealnl':l1l ~tr;lIeHie.,: for exallJple. ir1!r.I\'e~il';l1
`
`
`
`
`
`
`
`
`delivery of [}'ciopho.'ph:lI11id<: would m~kc no sens,'. 11<'rau,;('
`
`
`
`
`
`
`
`
`
`
`
`the dnl!; requirl"
`h~p.1ti~· metal'olism tu it, active form 10 11<.>
`
`
`
`
`
`
`
`
`
`
`cffenive (sec bter). In Ihe p;!tknt wil h hCp;flk dysfunction 0,
`
`
`
`
`
`
`
`hepmit' fuilllTc, imp;rircd hepatic conjugmion aller.' Ihe mctalx)·
`
`
`
`
`
`
`
`
`
`
`hsm of doxorubirin and of Ihe vine" a! kal oid'. wherc", Ih~
`
`
`
`
`
`
`
`lIlicm<;oll1nl a("livmion of cyc/op'Jo,phamidc may he illlpaircd
`in rhi, din;c .. 1 ",uing.
`
`
`
`
`
`
`f~x(: retion
`
`
`
`
`
`
`
`
`
`EWTclion 01 cyloloxic a~ents occurs prcdominatHly in Ihe
`
`
`
`
`
`
`
`
`
`
`kidneys and liver, and abnollnaJities in the' (Illiction of eithel
`
`or b0 111 tlf~an., Illay innueoct 1 ~ pallem o f loxicily.'1 Hen,,1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dy.,funetion p;!rticularly affect.' Ihe di'posilion of Ihe platinulll
`
`
`
`
`cOlllplexe,. nwt hotrexalc. and blwmyrill.
`
`
`
`
`Fal"lors Modif.\'inj!, J>harmacokinclics
`
`
`
`
`
`
`
`
`
`
`
`t\h~{)rplion of (i ru!!s Illay he aifcclcd by d i.'C,ISC' o f Ihe g1l'(cid:173)
`
`
`
`
`
`
`
`trointeslin,,1 tract. hy previous .wrgiral pnx;cdu n:,. hy colll·
`f1<,un(!, th ai ,'h"nge Ihe pH .. I' th~ ~ut. hy coad illini.wation <lr
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`othcrdrup. <lnd hy ulher f"clO" . ~, I ' Di, trihulion C<lll he inn u(cid:173)
`
`enced hy di,ea,c ,Wle" ,ueh a, t";.lrdi:K ta;ltll'e, a~l·ilcs. pleuraJ
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`eihl,i()n. ;lnd edcmu. and by Ihe c{'admini.,tralioll o f .'Uh"atKC~
`Ih"l ,."n di 'pian' ('(),"",."",I, (rOIl> hinding In ",rUn] "Ib"",in. I.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A~~ and amounl of ad ipose l i-'.\II~ may h",'c an impa,'1 on the
`
`
`
`
`
`
`
`
`
`clcaralK'c and tu~i~ effect- of (:ylntnxic a~enh . For exall1pk.
`
`
`
`
`
`
`
`
`
`obc'ity "PlleillS 10 reduce Ih~ deanlll~e of doxnrnlHl'in in
`
`
`
`
`
`
`
`
`
`
`
`"dulls,I .' "II hough Ih~ imp"ct "11 tf>xicily of the tlrug. i, 1I1l!: lcar.
`
`
`
`
`
`
`
`
`
`Age rn"y alter disjl(».;lio!l of dllX<1m/)u .. in: fl'r cxanlple, Roher!
`
`
`
`
`
`
`
`
`
`
`"nd Ho .... mi I ~ IlclllOllstratcd rNJuced dCal"UlKe in older pal ienl".
`
`
`
`
`
`
`
`C\llll jlared wilh younger l'ollul1\ (Char, 29). Nutnemu, fal'IHr'
`
`
`
`
`
`
`
`
`
`
`
`"fk(:t th" ralC til which drugs M( 1ll"lilhoh/Cd hy l'ylochr"llle
`1'450. '7 M"ny l'<llllpnUll(h C;'!l in<iJC" ('yl<xh r<)llle P4~(I. incl ud(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`
`ing p/t<:lwbarhilol and hyd,l1llllin, dllorinaled hydl"(",,,"il<'n ill (cid:173)
`
`
`
`
`
`
`
`
`,<'diciue." f, ... ..-J add iliv,". "nd <'"nino!;l'lls rrcsclli in lobti",'"
`. ~nll)~ c . SOllie allt ineopJ"'l i~' ;I)!crl.' lila), inllihit drug melal ..... -
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`li'Ill, IK a, Ill"y th e prc't:nce nf h"p,nic dl'",",e. "') E"'Tetinn " f
`
`
`
`
`
`
`
`
`
`CnIJlp,)lmds hy the ~idney, dqlCllrJ., heuvily , l]l renal fWIL,ti"n
`Coinddenlal l.dnllui,trall"n "I' lwnj'<HlIld' Ihal CIII ~'(lIn[>ek
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`lilr IUhlll"r )"<.:ah.,orrtion may arkCI renal de" ranec or l'crlain
`
`
`
`
`
`
`
`
`
`
`
`~" "Jl(~lllJl(h,'" a~ lIH1y urillary pH If Ih,' (1l1ll1~ ""ld i, "hie 1(>
`
`
`h",'olllc i,'nl/nL "
`
`
`
`
`1\ IEC HM,' ISI\IS (IF IH{l)( ; HESIST!\i'.C E
`
`
`
`
`
`
`
`
`
`S,"','I""I 1I1~,'h:mi'nl' Ill' rc,j,wIKl' to l'yt'"lo,i<: dl~lllolh,'raI'Y
`
`
`
`
`
`
`
`
`
`
`
`are' ~n"wn ( T"hJ~ \ -11, III ~~lIn" l. the.,~ 1JI~<"hanl.'III' ran I~
`
`
`
`
`
`
`
`
`
`cj:!ssirtcd onlh<, ha, i, o f rdlular di'lrihulioll. IlIlr"r<'llular fJ<' (cid:173)
`
`
`
`
`
`
`
`
`
`
`
`
`tors Illdud" 1110", tll;ll ad:1I III,' ccll Mlrfa<:e, other, willilu Ihe
`
`
`
`
`
`
`
`
`
`
`
`(')''''pl,l>]ll, ,HId tho.'.C fllnc lioll i ll~ at til<' il'vel " f thc nucleus. In
`
`
`
`
`
`
`
`
`
`
`addition arc extrJcdJular fa~ t nrs, slich a~ tho.,e th"l "ffcC! Ihe
`
`
`
`
`
`
`
`
`d i' lri)'uti"'l and IHcl:lholi.'lIJ of the drug". including. ('olllpclitNs
`1('r ('dlula r tnltl~p', ·t IIlc<:hani,m,.
`
`
`
`
`Somc cytntoxi(' a!;enl' can oc exported fWIll tumor cells
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ihrou~h a me('h'1Ili'nJ h"sed on Ihe cellul"r ,!,rrace, Ihe ',,-called
`
`
`
`
`
`
`
`
`
`
`Illullidrllg dflll~ I'ump. whkh i, characterilCd hy Ihe c,\pression
`
`
`
`
`
`
`
`of a ,pecilir I 7n·kd prolein wlllplex, P ~Iy<", .prot c;n . ~: I n''~,ti ­
`
`
`
`
`
`
`
`
`
`I!utnrs inili"lly delllon'lrated thai re~j'<lI1'c 10 thc cdlil lar cffecb
`
`
`
`
`
`
`
`
`
`
`
`
`of "I-'~IJI' '" diVerse ," Ilw vilK'a albloid.,. <lclinomY~'in D. and
`
`
`
`
`
`
`
`
`
`d<lXOfUhicin i, fc'(h":cd in normal and Illalig lla rll cell, Ihal ex(cid:173)
`P'-