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The Influences of Cytotoxic Drugs and L1210 Suspension Culture Density on De Novo Purine Synthesis Joyce Ann O'shaughnessy Yale University

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The Influences of Cytotoxic Drugs and L1210 Suspension Culture Density on De Novo Purine Synthesis Joyce Ann O'shaughnessy Yale University Yale University EliScholar – A Digital Platform for Scholarly Publishing at Yale Yale Medicine Thesis Digital Library School of Medicine 1982 The influences of cytotoxic drugs and L1210 suspension culture density on de novo purine synthesis Joyce Ann O'Shaughnessy Yale University Follow this and additional works at: http://elischolar.library.yale.edu/ymtdl Recommended Citation O'Shaughnessy, Joyce Ann, "The influences of cytotoxic drugs and L1210 suspension culture density on de novo purine synthesis" (1982). Yale Medicine Thesis Digital Library. 2999. http://elischolar.library.yale.edu/ymtdl/2999 This Open Access Thesis is brought to you for free and open access by the School of Medicine at EliScholar – A Digital Platform for Scholarly Publishing at Yale. It has been accepted for inclusion in Yale Medicine Thesis Digital Library by an authorized administrator of EliScholar – A Digital Platform for Scholarly Publishing at Yale. For more information, please contact [email protected]. 5079 (Title of thesis) for the purpose of individual scholarly consultation or refer¬ ence is hereby granted by the author. This permission is not to be interpreted as affecting publication of this work or otherwise placing It in the public domain, and the author re¬ serves all rights of ownership guaranteed under common law protection of unpublished manuscripts. 3/H Uj- Date p J .i'' :irJ VF W'i-i Digitized by the Internet Archive in 2017 with funding from The National Endowment for the Humanities and the Arcadia Fund https://archive.org/details/influencesofcytoOOosha The Influences of Cytotoxic Drugs and L1210 Suspension Culture Density on de novo Purine Synthesis A thesis Submitted to the Yale University School of Medicine in Partial Fulfillment of the Requirements for the degree of Doctor of Medicine to be awarded in May, 1982. Joyce Ann 0*Shaughnessy Hed L/b- <113 Yi^ 3079 Acknowledgements: I wish to thank Ed Cadman and Chris Benz for four years of guidance and support and for the opportunity to work with them, and Robert Heimer for his assistance and advice. I am grateful for the funding provided by Ed Cadman and the Yale School of Medicine Summer Student Fellowship Program which supported this work. 3 ti ‘3n; : iqa i won'- - ’hi?' ■^rr^,, 3 ,,?iw I !''n£ tj'3;a ■to J5'j • pv -ijL.'ol: ■tti'i :vS" ■^•j t tr, i. - -••"’40 snt “iJij'i 9'^ij ->_rrl 'Tf; ■ - ,.-*-♦* 1.*, 1 't S3- CT^ txrjj I 9 r‘: _ r ■EiTl.fcijO 2^,5 7- ia.ntni/S 1 XlOvV 'r ^ f ■»• 39 TTOQ.^Ue f 3 ABSTRACT Pretreatment of L1210 cells with methotrexate has been shown by E, Cadman et al to enhance intracellular accumulation of 5-fluorouracil and the formation of metabolically active fluoropyrimidines, Sequential treatment with methotrexate and 5-fluorouracil resulted in synergistic cytotoxicity. These effects of methotrexate were correlated with increased intra¬ cellular levels of PRPP(5-phosphoribosyl-l-pyrophosphate), the cofactor required for the conversion of 5-^luorouracil to 5-fluorouridine-5*-monophosphate(FUMP), Methotrexate is a potent inhibitor of de novo purine synthesis and it is likely that methotrexate’s anti-purine effect resulted in the increased PRPP levels and therefore in synergism with 5-^luorouracil, The anti-purine effects of 24 cytotoxic agents were measured l4 by quantitating incorporation of 1- C-glycine into purine bases. Possible synergism between each of these agents and 5-fluorouracil is discussed based on the agents’ mechanisms of de novo purine synthesis inhibition. It was found that de novo purine synthesis progressively decreased from peak values in early log phase grow’th to/N-/ of the maximal level during late log and plateau phase growth of L1210 cultures. Increasing concentrations of exogenous hypoxanthine, a substrate in the salvage pathway of purine biosynthesis, were shown to progressively decrease de novo purine synthesis, making increased utilization of salvage purine synthesis along the growth curve one possible explan¬ ation for the observed decline in de novo purine synthesis. J n:^»9o B£';t .n^lw 3,;'“?'? \6 ' . .Tft.iiirf;?X'2)a.f- -T?-*. li. oi’ Is i"?' *S \d nwodB ;.v.r?-'5 r f Ic rto rtr.^ XioSTSiJOaOif.Il-’i to f»: X-, ■ 'C '.fvia ii. rr?* ‘ ri,^m*dbJi^ttv<lon03^l\ ■ iT :z:.ijTu*v^ crJ'Hl-^'^vrv : .i ili DDfiji/oiotrlt-^ - I -ni Hj-rw c«^^•a'Xlri■'Ic.o y iv - ecrsArtuto J.-:.- . , ■> r .-.,\'.;p,-:-.-' to elrv®! tjbIj;/IX#o 0^* Ii3 2*ri;->'r<3ij It-$ to '“'oi juvnoo lot £>®':ijyp«i notoatoo si )s>Xsdqt}0;1)C|0£K)«i-*^>T-9nibI'Xi;o'XoyXti*^ si fi>£ si®9f{-*.T^B ^rtin/q avart .efc to TO'^Icfirini ifcifttoq Di'Z:s!^z£)f(,' sdij- ,tx bGtXwadT: t'j'slt® B* if^exsiTodStna tadt .i:iD£'i;i-D-!-^o:'r-.- '.'Jiv rri e^oteTedi- l»na aXarel rG'T'.'xi£S'-'r w oi;xc*v,-Y,o to aco^tt# tdT Gi'T--;;q- o . 'ri- ;.jixr,YXg-i to :ioi^? .•oq'toon!: i*nitst'irna*/p :;LS ?-.‘r..,^: £.5G:1- to nc-32 riijfyrfotf tnci.g'ioiry.a alotsao*? .avacd £jjai'is1wG(n 'stfiG^js •='ilj rto b'g^^scf Dstaauoaib llorxwoioi/It-2. .rroi£ sxesifvnv.a affltyq ovon »Jb to ^nl'iuq cvon eo Tfidjf Onwot aaw &X y. - ■'■ t>tc .'*-^0v- nrwo*:^ aas.Aq 30! rr: sat/Xxiv jf#»q motl b®8a«'Xo#b ^ rwo'X]i uiTsts.'t -l i* ^oI oJaX ifft^ b IdvaX XjmbIj^ibo td^‘ to 5L£Ojrt£sc>X£' to anoid'siJrraortoo igiiiaiotonl iSa’tt/iT'iiJO OXSXwt to an^’iL-q ''oswntsq a^iovlss ©rf^ ni eJ*n;?ecii/a 9 ,i«tIfltrt«xoqX'^ cvon ob ©aetj'TQsh vIovlaae'i^O'Tq of rtvrarra •aia^d^q^sold s^fivlsa to rtold'^fiiXir/o‘ b3a«sior5-. srjiivjfitt , »i8'dri3'rr'^8 »niiuq -aoXqxe ^loiaaoq sm svzyo ^nolB • tfni'itrq .8/5y»d;riT^s aaiiyq ovon ®b ni oaiXo^Jb fesv-r^ao'-? lot nolfM 4 A reduced rate of de novo purine synthesis secondary to length ening of the cell cycle from early to late log phase growth is discussed as a second explanation. Finally, a progressive decrease in cell volume with increasing culture density re¬ sulting in a need for reduced overall purine synthesis to main tain the required intracellular purine nucleotide concentra¬ tions is discussed as a third possible explanation for the decrease in de novo purine synthesis. The anti-purine effects of cytotoxic agents must be interpreted in the light of this natural progressive decline in de novo purine synthesis during exponential cell growth. J ■ j - ■ Ci3i:'i:0‘-sz ovoi\ Iter #i-\a'T ■sr;3X O' ;roit -.■.,■ I£9'. M-j' -•'lo'i'c ; ».J,; U;. •' . io-. o'•riOisXtjX'i b«a3e3«i:b « .Is. i-jtTii T r*.^4 iJ .'-VTOiii fitfiW S;..':jXov XX^^j rti i ■ :■’ .•.;.. i./- ..i:5'iov‘3 'roX beii»i e jrri^’Xy •h' JiA' - . £>-rto'’i :L > .''o.. • -^zi:jLl^oe't. iU nie .v.>: .;.u-:.i.:;.. c ■ _' . ie-.o- ;:'3iriX s Gfs bepsyi-?.ib eX fcitoi tiT -y 3 . r:-j-M s-riX sTj* >■• .rt r^s dni^i/c vfon ■*£) cU eta^'xa# - --* ”• - .2 ;.v -*■ ■ •.-,! ed .T?jj7} jpjfifcais qixo^o^o * oce .vn. lv*-. rri *t;xIo9& »vjtast'i^cj'xq IsTuXs .1X^45 X^iJ’n^aoqx® anl*ta/ 1' 5 INTRODUCTION In treating cancer with cytotoxic drugs, clinical trials have shown that combinations of drugs generally result in better tumor response and patient survival than does single agent chemotherapy. Until recently these drug combinations were most often chosen on the basis of different proposed sites of drug action, different toxicity or simply empirically. Rarely has sequential drug therapy been designed from known biochemical parameters that would facilitate effective drug activation or other advantageous interactions between drugs or between natural metabolites and drugs. Certain sequential drug combinations have demonstrated synergism in inhibiting the growth of animal tumors(l), and the biochemically rational design of sequential drug therapy has become of interest to many investigators. Methotrexate and 5-f’luorouracil have been used success¬ fully both singly and in combination in treating many human neoplasms including breast and colon cancer(2), Ed Cadman et al have shown that methotrexate pretreatment of L1210 murine leukemia cells in concentrations which produced near maximal inhibition of dihydrofolate reductase, enhanced intra¬ cellular accumulation of 5“f‘luorouracil(5-fold) and increased 5-fold the formation of the 5-fluorouracil nucleotides, FUMP, FUDP, FUTP and FdUMP, These alterations correlated with synergistic cytotoxicity. In cells pretreated with methotrex¬ ate in concentrations between 0,lpiM and lO^M, intracellular 5-phosphoribosyl-l-pyrophosphate(PRPP) pools were increased between 2 to 8 times over control values. The increases in :(ti-<'r. s?ix.''>.To^"Yo :isi%s -lACimiD :^hltS9Vt''ii^ ^. ■• .'J :x.;'r-sr;'is 3'ifr.o.tn^riTw'^:rt‘i »va . !<■■••.•■'■ ■’ ^ h n:'::-:'7 ...i'.'-L"/7Ui'» ofTS #iirr^<y!ife^T *so.W- '! ■ '•••. .:r-!.':(rc;: lirn^ . ■',■ Mrotii'o'vq .rnr^^ri^r i.i''^ '-o *^i'T c,'- ^.fOJ ;> .,.*-„^,i. 'irt) j.Lto-'^' ^r-'s^c'fa ,noi.Toa S*''**^’ ..;; :- . .>r ,■'. i,b, .?nc*i/p«a B«<f . 'ri: ■"% 1 z ' •!- e **-/ 'i;;." .ii/iiw' ^ .'■'tf-r•,wjn!,i»'^ t.«0:^'iSllrtOOll ■ ■' --. rf- i' 'SnoiT. '^!»7^*‘fc '■ ai,7iJ5tiV.-vV/^,fe .-jfj ««i’tjVjf I'd) • '■■■■ ■ '!■ .r;p,)''!t.' b:v» ^■■'3,riX^;,-.,j :^,^5 i's'iwtar!' rt( yir.' j.i. _ r . :^?i,,. ;^ rr--*- ,ri L/ff isr^d J,i3 a{TOit^J3WT.f'rfW^bts jp/lj -r . .• .rr v. ... “r'i''’ai.Tc-i:'■ ••.-^.x , ■ I ^ -Df,..'-X X.jtTjIft* to.
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