HomeMy WebLinkAboutCOM 0314.057 1996-1998 • r RECENED
a_~"~+T
Antineoplastic Activity of Cannabinolds'•' nmp -~--y__.By...---._...-_.......:`
in ".11.ta~Q7.-----
County Council ~`•r'
A. E. Munson, L S. Harris, M. A. Er,~dman; W. L. Dewey, and R. A. Carchman ° p_
SUMMARY-Lewis Lung adanoearelnama growth was retarded carcinoma, leukemia L1210, anti B•tropic Friend leu-
by the oral adminlstretlon of A+•tatrahydroeannabinol (.1"•THC), kctnia.
~"•telrahydrocannabinol (a^•THC), and eannabinol (CBN), but /n vivo rpNUnr.-Lewis Iwtg tumor: For the nminte•
not cannabldiol (CBD). Animals treated for 30 comeeutlva days nand of the Lewis lung carcinoma, approximately
with o+•THC, beginning the day rftar tumor Implantation, I•nun^ Picccs of armor were transplanted into C57BL/0
demonstrated • dose•depandent action of retarded tumor mice tenh a 15•gauge trocar. !n exl7eriroents iuvoh•ing
growth. Mice treated for 20 conseeullve days with A^•THC and cl7entotl7erafly, 19• to IS•da)'•old tumors were excised,
CBN had reduced primary tumor sire. CBD showed no Inhlb4 cleared of debris and ncaouc tissue, and cut into small
lory eHact on tumor growth at 14, 21, or 28 days. s"•THC, (ragntenls I nfm'). Tumor tissue was then placed in
~+•THC, ¦nd CBN Increased lha mean survival Ilme (36% at U.25 ; trypsitt in Dtrlbecco's meditrrn tvitlt 100 U penicil-
100 mg/kg, 25°/, at 200 mg/kg, and 27% at 50 mg/kg, re• tin/ml and 100 pg streptomycin/ml. Alter 90 minutes'
speetlvely), wheresa CBD did not ~"•THC administered orally incubation at 22° C, Irypsin action e•as stopped by the
dally until death In doses of 50, 100, or 200 mg/kg did not addition of complete medium containing liwt•inacti-
Increase the IIle•spsns of (C578L/6 x DBA/2)FI (BDFr) mice rated fetal calf serttrrt (final concer7tration, 20 Cells
hosting the L3230 murlna leukemia. However, s"•THC admin• were washed nvo times fn complete mediwn, enumerated
Istered dally for 10 days slgnifiuntly Inhibited Friend leu• in a Coulter counter (\(odcl ZB,) or on a hemocytometer,
kemla virus-Induced splanomegaly by 71^/o at 200 mg/kg n anti resuspended in senundree medium at a concentra•
compered to 90.2% for aetlnomyeln D. Experiments with bona lion of 5X IU" cells/tnl. Next 1 X 10" cells were injected
marrow and Isolsted Lawls lung evils Incubated In vitro wtth iut into the right hind gluteus muscle, and drugs admin•
~+•THC and ~"-THC showed a dose•depandent (30•<-10•r) istered as described in •'Results.° Standard regimens pro-
Inhlbltlon (80-20%, raspedlvely) of trltlated thymldlne and vitletl fur IU conse[utice daily doses beginning 29 hours
~'C•urldlna uptske Into these calla. CBD was active only In after tumor inoculation. Body weights were recorded be•
high eoneentratlons (30•").-J Natl Csncer Ins[ 55: 597-602, [ore tumor inoculation and weekly [or 2 weeks. Tumor
1975. size was measured w•eckly for the duration of the cx(7cri•
men[ and converted to mg tumor weight as descrbed
Lnestigations into the physiologic processes affected by Mayo (!0).
b)• the psychoactive constituents of marihuana [o+•tetra• Friend leukemia: B•tropic Friend leukemia virus
hydrocannabinol (~+••I'HC) and p"•tetrahydrocannabinol (FLV) teas maintained in BA[,II/c mice. and drug evalu-
(~^•THC)] purified from C.nrnmLir mlivn arc extensive anon performed in the same animals. Pools of virus wcrc
However, only recently have attempts been made to prepared from the plasma of mfce given FLV anti stored
elucidate the biochemical basis (or their q•lotoxic or at -70° C. In experiments with FLV, 0.2 ml of a 1/20
cptostatic activity. Leuchtenberger ct al. (2) demon. dilutimt of plasma (derived from FLV infected mice) in
strafed that human lung culuires exposed to marihuana nudium teas inoculated ip into BALB/c mice. Cannabi•
smoke showed alterations in DNA s}•nthcsis, with the voids wcrc administered orally daily for 10 consccu.
appearance of anaphase bridges. 2innnenuan anti dfc• rive days beginning 2.1 hours after virus inoculation.
Clean (3), saidying macromolecular s}•nthesis in Tatrn. Tteentt~•four hours after the last drug athninixtration, the
hrrnenn, indicated that t•ny lute concentrations of o+• mice were killed by cervical dislocation. anti the spleens
7`I IC inhibited RN:1, DNA, and protein synthesis and rcnu7vctl anti wcighetl. \lirc not git•en FLV wcrc treated
produced Cytolysis. Stenchet•er et al. showed an in. as described abot•e. to evaluate possible drug-induced
crease in the number of tlantnged or broken chromo- splenonu~aly.
somas in chronic users of marihuana. ~^•THC atlminis. [.1210 eukemia: The murine leukemia L1210 a•as
recall iv inhibited bone marrow leukopoicsis (S), and maintainctl in DBA/2 mitt by weekly transfers of 10^
I:olodny ct al. reported that marihuana stay impair ccllx derived from the pcriwneal cat•iq•. In these cxpcri•
ceaostermte secretion anti spermatogenesis. Purtherntore, meats, IUs Ieukentia cellx were inoculated ip uuo
• Xahas et al. (7) shoteed that in chronic marihuana users (C!i7li[./fi X DIl:1/2)Ft (IillF,) mice, and The mire were
there is a decreased I}•ng7hot}'te reactivity to mitogens as treated daily Ior 1D consecutive [lays heginning 2.1 hours
measured by thymidine uptake. 'These and other (3) after tumor cell inoculation. A[ean sun•itml tiara ryas
obscrcations suggest that ntarihu:ma (~":I IIC) interferes used as an index of drug activity.
frith vital cell biochemical processes, though no definite !rr vino calf t)vternr.-l,eteis Iwtg tumor: R'e obtained
mechanism has }'et been established. A preliminary re- isolated I,eteis lung rumor cells by subjecting 1-mni' sec•
port from this laboratory (9) indicated that the ability o[ lions of tumor to Q25 ; trypsin at 22° C anti stirring far
~'•l'IIC to interfere with normal cell functimts might 00-90 winutes. After tr}'psiniration, the cells were ttntri•
prose e(ficacioas against neoplasms. This report repre•
tents an effort to tell various cuntabinoids in several , Reccirr,l Drcauber Re, 1971; acrepirJ It(ay 70, 1975.
in t'it'oantl in vitro punUr Sylletil5 to delenninC IItC aSuppe,nal by Public Healtb S<rrice gent UAOOIJO fmrn the
kinds of tumors that arc Seit9i live to 117CrC CUntlx)u ittla National Inrtiune on Drug Abux. Itcahh San i<o k M<nul
and reveal their possible biochemical sites of action(s), 11nhh AJnrini.tration: by a gran Irom the A1<aander and \la-
garcl Stee'art "rrurt Fund; and by an imtitutional grant from the
• Amrrinn Canc<r Society. •
MATERIALS AND METHODS a Drpanment or Pharmarolo~y anJ tlm AICY/PCU Canr<r Cen-
ter. M<di<al Coll<ge of t'irgiura, \'irgiuia Com mona~ea lih Unit<r•
'lire tumor systems used wcrc the Lewis lung adcno• sity, Rldunond. va. zsrre.
LOUR CAI. OF TIIE NATIONAL CANCE0. INSTITUTE., VOL. 55. HO. Sr P'r r.alerR 1975 5~7
FIRf~• TtiIRfF PAGfS~ 4o~a? 1T4 3~~ 57
)rtb I<~ U S~
$et[. Ybt ~101enied ~
~t, JUN l 61991
s off • 7+tUNSON ET' A4
[aged (1,000 rpm for 10 min) and tva_~.ed twice in Dttl• CH3 CH3
Uecco's medium containing 20% heat inactivated fetal calf
scrum. They were then reconstituted to lOr cells/ntl in OH OH
DulUecco's medium containing, for every 500 mh 5 nil of
200 mnt glutamine, 5,000 U penicillin, and 5.000 µg strep-
tomycin, Ttnnor cells (3-6 ml) wire dispensed into 25-nil CSHII(nl I C5H11(~)
Erlenmeyer Masks and preincubated with either the dntg
or the drug vehicle for 15 minutes in a Dubnoff metabolic g 1
shaker at 37° C in an atmosphere of 5 ~ COz 95% Os. ~ -THC, ~ THC Oe-THC, ~Itel-THC
Alter preincubmion, 10 µl triuated thymidine (rH•TDR)
(10 µCi, 57 Ci/mmole; New England Nuclear Corp., Bos-
ton, Afass.) x•as added to each Mask and incubated for vari•
ous times, after which 1•ml aliquots were removed and CH3 CH3
placed in IOX75•mm test tubes containing 1 ntl 10 ; ~ OH OH
trichloroacetic acid (TCA) at 4° C. The 1'CA•prccipi-
tated samples x•ere tjjten filtered on O,45•µ Alilliporc fil- ~
tars and x•ashed tx•ice with 5 ml of 10 ; TCA at 4° C.
The filters were transferred to liquid scintillation t•ials. I CgHtl(n) ~ C5H11(n)
and counted in a toluene cocktail containing Liquifluor OH
(New England Nuclear Corp.) (4 liters toluene to ICO ml
Liquilluor). Samples xere then counted in a liquid Connobinol (CBN) Cannabidiol (CBD)
scintillator.
'irxr~ncvxr L-Strucwres of the tour major caunahinoids.
Bone marrox•: Bone marrow cells were derived from
the tiUias and fibulas of BDF, mice. One ml llulbecco's substances were stirred x•itlt a lass rod in a sonicator
medium containing 1 U heparin/ml teas forced through until a good suspension xas achtoved. Sufficient distilled
each bone by a 1•ml syrin with a 2f.gaugc needle. The
cells were washed three ut~»es, nucleatttl cells were enu• water was then added to make the desired dilution. Con•
meramd on a hemocytometer, and cell viability x•as aster- ~entrations were routinely checked with a gas chromat•
rained b}' tr}'pan blue exclusion. Cell number was ad- ograph. hen Emulphor-alcohol x•as used as the t•ehi•
jested to 10' cells/ml with he mrin•(ree DulUecco'a cle, the desired amount of cannaUinoid was sonicated
medium and incubated at 4° C ~or 15 minutes. (lone to a solution of equal volumes Uy abwlute ethanol and r
marrow cells were thth dispensed (3-5 ml) into 25•ml Emulphor (El•62U; GAF Cor New fork, 1~.Y.) and
Erlenmeyer flasks containing the teat drug or the drug then diluted x•ith 0.15 N NaC~ for a final ratio o[ 1: i :4
vehicle. This preincubation period ryas followed by tht (ethanal:Emulphor:laC1). i
addition of 10 µl aH•TDR and cite procedures done as RESULTS
outlined for the isolated Lewis lung cells.
L1210: L1210 cells were derived from DBA/2 mire as ERaets of CanmElnolds on Murln~ Tumor
described above. They were obtained from DBA/2 mice pr:
CHC, '•THC, and cannabinol (CBN) all inhibited
and inoculated 7 days before the experiment by the primar}• Lewis lung uunor grox•th, whereas cannabidiol
peritoneal cavity being Gushed with 10 ml DulUccco's (GBD) enhanced tumor growth. Oral administration of
medium containing heparin (5 µ/ml). The cells were 25, 511, or 100 mg Gr•THC(kg inhibited primary tumor
washed three times in medium, and the final medium growth by 48, 72. and 75 respectively-, when measured
~ wash did not contain heparin. The cells were rases- 12 days jsost tumor inoculation (table 1). On day 19.
periled at IOr cells/ml and treated as described above. mice given A'•TfiC had a 34 ;redaction in primate
Cells were routinely counted with a hemocytometer for tumor sire. On clay 30, primary tumor sire x•as 7G a that
the determination of cell viability x•ith trypan blue; for of controls and only those gtven 100 mgg Gr-THC/kg had '
Lex•is lung tumor and L1210 «lls, a Coulter apparaws a significant increase in sun•ival time (36
(ttlode ZB,) was also used- Itlice treated with D°-THC showed a slight x•tight loss ;
All other reagents were of the highest qualityy grade over the 2•x•cck period (average loss, 0.3 g at 50 mg/kg
available. Actinomycin D, 5.Ouorouracil (5•FU), and and 0.1 g at 100 mg/kg). This can be compared to cyclo•
cytosine arabinoside (ara•C) were provided by the Drug phosphamide, which caused xeightloss approaching 20
Development Branch, National Cancer Institute (NCI). (table 2).
Canrmbinoids,-The structures-o[ the (our compounds A"-THC activity was similar [o that of ~r•THC when
are shoxas in text-figgure I. All occur naturally in mari• administered orally daily until Jeath (table 2). Hotvecer.
huana and were chemically synthesized. These drugs as with A'•THC. pnmary tumor growth approac)tecl con•
.were provided by dte National Institute on Drug Abuse trol values after 3 weeks. When measure) 12 days lzou
or the Sheehan Institute for Research, Cambridge, Itfassa• tumor inoculation. all doses (50-400 mg/kg) of A"•TI IC
chusetts. In the preparation of the drugs, the cannabi- inhibited primary tumor growth betx•cen 40 and GO'%~•
voids were complexed to albumin or solubilired in Significant mhibaron x•as also seen on day 21, which tra+
Enudphor-alcohol. Both (reparations produced similar comparable to cyclophosphamide-treated mice. Although I
antitumor activity. With albumin, the cannabinoids were this was not the optimum regimen for cyclophosphamidc•
prepared in the following manner: A stock solution o[ it was the (zositire control protocol provided Uy the NCI
150 mg cannabinoid per ml absolute ethanol was mach (11). All mete given p"•TH survived significantly longer
Six ml of this solution x•as placed in a 200~m! Oask. The than controls, except those treater! with 100 mg/k8• Mire v
ethanol was evaporated o0 under a stream of nitrogen given 50, 200, and 400 mg/kg pr•THC had an mcreasecl
and 2.100 mg lyophilized Uovine scrum albumin ((SSA) life-span of 22.6. 24.11, and 27.21, respectivel}•, as com•
added. After the addition of 20 ml distilled water, the pared to 33 : for mice treated with 20 mg cyclophus•
` ANTICANCER ACTIVITY OF CANNAAINOIDS 599
/ TABI,B I. Effed of 'NC on tams protof)r and aurpipol lime of mica hon. Levin luny portinoma
Tumor welghla (g) at
Treatment Dees Hody w•tight h[ean survival Incrcaeed
mg/kg 'change (g) / 12 days • l9 days • 30 days • time (dsye) life-epsn, %
Control (BSA 7.5%)------ - +1.5 892tIb0 3,4581252 5,883}873 25.8}1.3 -
t 5•-TIiC._•______________ 25 10.9 4G8(t107 ~ 2,363}148 ~ 4,3371278 a 30.312.0 17.4
/ p b0 -0.3 253t118e 2,1681105• 4,8.91) 27.4f0.G 8.2
(8) (8) (I)
p•.TIiC_________________ 100 -0.1 221f98e 2,307t382e 4,888t312e 35.Ofl.ld 38
• Group of mica Wert Inecult4d Im del, 1X10• Lr.b Iona eslh toil veiteJ welly br 10 dtya allh e••TIIC.
t Nho6 body welRht ehinib albs 10 dsye of Irnlmenl.
• Post lamer ImpbnY; tumor welthM wart deflved tram mtuurem<nt of minor ind miner ntr. Tdun to momdai: number e(ml<e ue Indioted in pinnlAnn.
r P <0.08 a eompirtd b <on4pb.
TAet.e 2. ~j7eH of n'•TIlC on Tumor prolrth and aunilnl time of HDFt mice hotline Leln'i loop cprttinonm
Tumor w•eighUt (g) at
Trenlment Urme Body w•eiRhl i1(esn altrvival Incrcntetl
mg/kg change (g) i l2 dnya • 21 dsye • lime (Joys) lileapnn,
Control (BSA 7.b%)___.______ - -I.8 O21f30 4,880~38U 30.StU.9
(30) (3U)
dl-T[iC._.____,__••_•••.--_. b(1 -0.9 238}48 • 3,IWt2i4 a 37.4}1.7 a 22.0
r IOU -3,4 184}38 a 2,TJ9t238 d 34.311.9 12,4
(71 (7)
nt-THC•._-.____•-..-.•._•_. 2IX1 -1.8 174153 • 3,IBSt389 a 38.011.9 a 24.6
(8) (8)
ot-TFIC_________________•_:_ 4W -3.3 235178 a 3,1941413 d 38.811.2 ~ 27.2
(81 (8)
Cy'clophoephsmide.__.. 2U -4.0 0 e 2, 94Ut 1U4 a 40.811.8 ~ 33.0
(81
Pyrall eopolymer_____________ SU +0.3 122188 • 1,Si8fli4 a 42.Sf3.3 a 39.3
(8) (A)
• GrouN of malt BDF, mI<r .err Inaculiled Im whh 10. 6wla IenR rorrinomi eelb ind Weed mdly dilly rllA a••TIIC untll.dnth. CyelephoepMmlde inJ pynn
copolymer .ere tdminhlered Ip for 10 eot+eeeully dq•i heilnnlnR as houn titer bmor htoeululon.
/ w'hola beds weitht ehintn after 10 diyr of IrcUn,ent. _
• Port lamer Imp6no; tumor weliMa arts dnhrd Irem mawnment el major ind minor tamer un. TJun m mnmtee; number of mist ne InAI•
~ turd in perrnlFuu.
• P <0.08 a compared to eoNro6.
TaBi,e 3.-F.Qrrl of ClJA' on Olmar prcu•th and aunirnl Time in l1DFt mitt hoelinp Lrlni loop rarrinoma
Tumor wrighln (g) sl
T Trenlment Dunn Ilmlp wcipht \lenn anrvivnl Inrren.•ed
~ mglAg ehnngc (g) / 14 dnya • '24 dnya • lime (dnya) lik-npan,
Cutttrol (DSA 7.5 +8.3 1,2`IAf 140 5,52(IfSGO 28.011.3
CItV (211 (21)
25 -O.G 11G5f 140d 0.74:1 t37U 2U.Ofl.2 12
(R) I~1
CbY_______________________ LtI -11.0 6ibfllbe b,i U!It?!11 33.id:1.6 2i •
(G> (a)
Clt~ 1W -2.c z99dals• 4,R43t4c2 2r.8t9.9 3.5
(7) (7)
• Grm,pi of mice Inotolited im with 1X10• Lewlr Iona eelh ind treated orally dilly with d••TIIC or CAN until dn1A.
• 1\'hola body' weliht ehintn iUer 10 Jq~• of Irolmenl.
• Pmt tamer Implmti; wmer we4hu .ere derlred Irem mnwrrmrnt of mibr and minor tamer im. t'Aun ve meim See: number of mks irr indl-
r11M1I In pe•r NAI<Ir.
• P <0.08 a rompued to eonvob.
phamitle/kg. Pyran copolymer, an immuno~rotentiator was obsers•etl on clay 2~1; hotrner, these animals did sut•
(1?) when administeral at 50 mg/kg, also significantly vice tie: longer.
increased the survival time of the animals (5J.5^:). C[SU, administered at 2r or 200 mg/kg daily until
CIlN, administered by gavage daily until dcaQi, dcns• death, showed no unnor-inhibitory fsrolxrtics as mcas-
atstrated antitumor activity against the Leivis lung card- ured by primary Lewis lung tumor size or sun•ival time
' noma when evaluated on clay 1•I post honor inoculation (table 4). In this experiment, CBD~treated mice show•erl
) (fable 3). Primary tumor growth w;ts inhibited by ii".: at enhanced primary tumor growth. liowever, the control
doses of l0U mg/kg on clay 14 but only by I I".: on clay :I. tumor growth rate in this experiment w•as decreased as
At SU ntg/kg, C11N inhibited rimary tumor ~rowdi by cmnpared to the (Irevious studies.
only 52e.: s+•hen measured on t~ay 14, and no inhibition Survival time o[ 1[UF, mice hosting [.1210 leukemia
nuNl/www.Y/YYaC.Cant/^11enIplBfClYhe011Bt9.hh1Y
• ~ Abshr~t fiom
Prenatal Mar~uana rxposure & Neonatal Outcomes in Jamaica: An
Ethnographic Study
By Melanie G Dreher, PhD; Kevin Nugent, PhD; and Rebekah Hudgins, MA,
Pediatrics, 1994; 93:254-260
ABSTRACT. Objective. To identify neurobehavioral effects of prenatal marijuana exposure on neonates in rural
Jamaica
Design. Ethnographic 5ekl studies and standardized neurobehavior assessments during the neonatal period.
Setting. Rural Jamaica in heavy-marijuana-using population.
Pm7icipants. Twenty-four Jamaican neonates exposed to marijuana prenatally and 20 no
nexposed neonates.
Measurements and main results. Exposed neonates were compared at 3 days and 1 month old, using Ure
Brazelton Neonatal Assessmem Scale, including supplementary items to capture possible subtle effects. Then
wen no significant differences between exposed and nonexposed neonates on day 3. At 1 month, the exposed
neonates showed better physiological stability and requited less examiner facilitation W reach organized states.
The tteanates ofheavy-marijuana-using mothers had better scores on autonomic stability, quality of alertness,
imtability, and self-regulation and were judged to be men rewarding for caregivers.
Conclusions. The absence of any differencxs between the exposed on nonexposed groups in the early neonatal
period suggest that the better scores of exposed neonates at 1 month are traceable to the cultural positioning and
social and economic characteristics of mothers using marijuana that select for the use of marijuana but also
promote neonatal development
~~[1 r,° ~7=1.~..L C~.t1 ~Yi L~. ~i' s~ ~tri~
Etmp Notion Xeadqumters
G7+~rLrtopAier G7aY, PrePr~r
343 Richmond Street, Suite 101
London, Ontario
Canada N(uf 3C2
(S19) 433-5267 Fax (319) 433-7725
World Wide Web: ht1n://aoba~com/-hemp
F.n?ail: kema.nation(abobozcom
~ '~A;
1
. .
. _
~~n.... a~.j£yL
i..ri v. '
. • .
• .hr. _ _ _
W WIrY1?n 'i..
. .(Y• ~•Y. r • 1 . II I. . •N 1.. ~ 1 ~ ~ V.,• vy • ~ ~ ? Y:M!!A••
K.,~... .Y.... ~y'.,. • ..i.. ..n....... w. ~.i i~rV~. '•w.r_I.. Y._•...r.r.. _..~..r , .1.~~.•.
~~j+ .•AKr _
~i '1.1• f.. .
• • ~..1.... ~1 • ~i
1, , '
w ..M +w
m.
a'
m '
m ~ ~ ~ kn~ oat
b nrwa tae
ro wa
Raola~ aaa
' oawl to
sson to
taWa ~e
wnw as
I~.~m:bex of dr~g~ad~:~#ed.ba~les -shag. I-
. ~ pY
BytlreAmxladedlaree~ -oo the isYod mrt xtte-oat•r»bst+aoa-.. pc }IDe Nemq} dater, ~ ,n . 7~mksbtofahaato~Owhhthen~s
BII,O - Soda! wotten m the Big ~ i rwmw b ga them dtog. disco+ard, m dIe ~ d show 5re to tae;allue (the pda oQ pot bas gone op so
a Idend ea rrppmsq a dremstia intaase in ttcsas~ before Ihh give biAh'1ms jart_ sit babies atb tnowh, said DD. high,' Westmotr7end said "I thinit a big
I rho t+as6a of ba>bia haw with dings in hed iti art b~ a third. s wine s>d d'mial stippviwr (m the pattof iris pcaplewho t~allywooldj~t '
theb syslrme, sod say a ~J is oadod The Bsbj SAFE peogsyw sddathe spte YWCA Fannly Sltppost Sawa. smote pot ca'c uTord i4 so they hoy toae
a w6ae esotbas and Ihdr nettfiams as go > of ifuhh satawod sbew 1,000 . sddt the hoa~iWs don't. red aheapa dtogs ftut have much gegta
drug ettpomre. e(teas oo e5e mast
a b1b~e a b1m 161It m the store risk for ebndes dcav,.sud l~tn• ~7, wotdd irlragfix we're mis9og who One 1&yearcld waaac who «cxdy
m as Osho, and !Fete r' tardy se Iamabe, duet tsmtdve aofica of dte Yaoas how tesoy at tbraa,' she said ~vn birth m a drag baby in }Tib was oared
sva0able slot m ml ~ ahem br a Big ttoepto& Big lslanad Sttbaamx.Abnse • : wh she cud ia.
tdend woteso who nteds hdp, s8d Muy Corral ' ' fa dIe part; .91o in5cs who Ceded 'yIt's ibe Daly way I as get away Sop
k Wamstxdaod eseaGVe distetot of the Tais yar, bermne of .fmmmg aab, nc~ P >amU7. had ooaine. a mdc io..tlrs,' s4e sai3 of ha fife be~a~8,yP~~I~~
. ' ~ tbOd YmYaiat Team a('Wert .lgfdif wt0 pmbebly,saeea only abort thcr iySirJdi .l'1y0,w,i~,~y~hgamipeS'twt~fIIC,~R1d~CI S 4~f aad lS{ 3~'.'"'".'W'
lfawau. waIDen, she sad, mash common, •'""'J Sand. with an t>503Ye hoy~.
"S a fap7uy opened ~ rho BigIslaadl y,~~, 9~ ~ w ~ ~hP 'Ihe 6igthing a dot is is cvapwhere, "11 tbae a anything that nceds m be
. we Catlld ~ h tight WWi Wstmordnnd ""'Y'ell 8mhatltlS6 aCpmitd Gdy'OAC~ 0( Ind If/6 Cbdpaad II~LPQy 8ppp~yg 10 }he ~ ~i'S CeM KaCt;{137Yi. ~ey
said `h's teaHy oa of ibo most ~8 fsa dagtxposad iolanb s yeay West. ~ she said, aD. ~n
~ money oa hclicanm it
needs lino we bare io terms of=ax~i aotehnd said Nov ~s u high g five at )o Rma; Wesammelwd said sbe,5ar brat-~;t?dicar,tp~pana'Fy~}~ttd..... .
.
~1a•bbla s elooth~
Maswh1q the ao! ottanrh " bxa'sere~ ia(yJa ihw art podtiiRfsa~~wbes'rtAOntnxdstletmat,we'pt9bad
I l ms's ~ ~ ~ ~ rnd6 fa cad herohc a place to acrid best"
. .
• .
{J. J.+•11 ?I•k.. • 'may-- I Ii .III V I{I tl l yyy~.~~
~~11 »~"'r :iJ i.... i'. i !It ..•ialyli ?t11i"tliti~K.".aL ,..,Rw T~dsr•, .{•t.~
M i ~ .C.?i
I ' t'a+3. k'...
s. LC ~ (F le i 4 J.' - 4 , ~ 1 L ?I i' . n f I t~~ , r - n
y ' . 1 1 .l I r.Mw. .I I {1 I ,11•. .IT 1 ~ 11M1(MI~I WSJ 1 G t
1!, '~1 .i.. ..I J... . I ~ p I .R~ 1 ~a.Y.
M.. ~~i .4.
•r~zr