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• r RECENED
<br /> a_~"~+T
<br /> Antineoplastic Activity of Cannabinolds'•' nmp -~--y__.By...---._...-_.......:`
<br /> in ".11.ta~Q7.-----
<br /> County Council ~`•r'
<br /> A. E. Munson, L S. Harris, M. A. Er,~dman; W. L. Dewey, and R. A. Carchman ° p_
<br /> SUMMARY-Lewis Lung adanoearelnama growth was retarded carcinoma, leukemia L1210, anti B•tropic Friend leu-
<br /> by the oral adminlstretlon of A+•tatrahydroeannabinol (.1"•THC), kctnia.
<br /> ~"•telrahydrocannabinol (a^•THC), and eannabinol (CBN), but /n vivo rpNUnr.-Lewis Iwtg tumor: For the nminte•
<br /> not cannabldiol (CBD). Animals treated for 30 comeeutlva days nand of the Lewis lung carcinoma, approximately
<br /> with o+•THC, beginning the day rftar tumor Implantation, I•nun^ Picccs of armor were transplanted into C57BL/0
<br /> demonstrated • dose•depandent action of retarded tumor mice tenh a 15•gauge trocar. !n exl7eriroents iuvoh•ing
<br /> growth. Mice treated for 20 conseeullve days with A^•THC and cl7entotl7erafly, 19• to IS•da)'•old tumors were excised,
<br /> CBN had reduced primary tumor sire. CBD showed no Inhlb4 cleared of debris and ncaouc tissue, and cut into small
<br /> lory eHact on tumor growth at 14, 21, or 28 days. s"•THC, (ragntenls I nfm'). Tumor tissue was then placed in
<br /> ~+•THC, ¦nd CBN Increased lha mean survival Ilme (36% at U.25 ; trypsitt in Dtrlbecco's meditrrn tvitlt 100 U penicil-
<br /> 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'
<br /> speetlvely), wheresa CBD did not ~"•THC administered orally incubation at 22° C, Irypsin action e•as stopped by the
<br /> dally until death In doses of 50, 100, or 200 mg/kg did not addition of complete medium containing liwt•inacti-
<br /> Increase the IIle•spsns of (C578L/6 x DBA/2)FI (BDFr) mice rated fetal calf serttrrt (final concer7tration, 20 Cells
<br /> hosting the L3230 murlna leukemia. However, s"•THC admin• were washed nvo times fn complete mediwn, enumerated
<br /> Istered dally for 10 days slgnifiuntly Inhibited Friend leu• in a Coulter counter (\(odcl ZB,) or on a hemocytometer,
<br /> kemla virus-Induced splanomegaly by 71^/o at 200 mg/kg n anti resuspended in senundree medium at a concentra•
<br /> compered to 90.2% for aetlnomyeln D. Experiments with bona lion of 5X IU" cells/tnl. Next 1 X 10" cells were injected
<br /> marrow and Isolsted Lawls lung evils Incubated In vitro wtth iut into the right hind gluteus muscle, and drugs admin•
<br /> ~+•THC and ~"-THC showed a dose•depandent (30•<-10•r) istered as described in •'Results.° Standard regimens pro-
<br /> Inhlbltlon (80-20%, raspedlvely) of trltlated thymldlne and vitletl fur IU conse[utice daily doses beginning 29 hours
<br /> ~'C•urldlna uptske Into these calla. CBD was active only In after tumor inoculation. Body weights were recorded be•
<br /> high eoneentratlons (30•").-J Natl Csncer Ins[ 55: 597-602, [ore tumor inoculation and weekly [or 2 weeks. Tumor
<br /> 1975. size was measured w•eckly for the duration of the cx(7cri•
<br /> men[ and converted to mg tumor weight as descrbed
<br /> Lnestigations into the physiologic processes affected by Mayo (!0).
<br /> b)• the psychoactive constituents of marihuana [o+•tetra• Friend leukemia: B•tropic Friend leukemia virus
<br /> hydrocannabinol (~+••I'HC) and p"•tetrahydrocannabinol (FLV) teas maintained in BA[,II/c mice. and drug evalu-
<br /> (~^•THC)] purified from C.nrnmLir mlivn arc extensive anon performed in the same animals. Pools of virus wcrc
<br /> However, only recently have attempts been made to prepared from the plasma of mfce given FLV anti stored
<br /> elucidate the biochemical basis (or their q•lotoxic or at -70° C. In experiments with FLV, 0.2 ml of a 1/20
<br /> cptostatic activity. Leuchtenberger ct al. (2) demon. dilutimt of plasma (derived from FLV infected mice) in
<br /> strafed that human lung culuires exposed to marihuana nudium teas inoculated ip into BALB/c mice. Cannabi•
<br /> smoke showed alterations in DNA s}•nthcsis, with the voids wcrc administered orally daily for 10 consccu.
<br /> appearance of anaphase bridges. 2innnenuan anti dfc• rive days beginning 2.1 hours after virus inoculation.
<br /> Clean (3), saidying macromolecular s}•nthesis in Tatrn. Tteentt~•four hours after the last drug athninixtration, the
<br /> hrrnenn, indicated that t•ny lute concentrations of o+• mice were killed by cervical dislocation. anti the spleens
<br /> 7`I IC inhibited RN:1, DNA, and protein synthesis and rcnu7vctl anti wcighetl. \lirc not git•en FLV wcrc treated
<br /> produced Cytolysis. Stenchet•er et al. showed an in. as described abot•e. to evaluate possible drug-induced
<br /> crease in the number of tlantnged or broken chromo- splenonu~aly.
<br /> somas in chronic users of marihuana. ~^•THC atlminis. [.1210 eukemia: The murine leukemia L1210 a•as
<br /> recall iv inhibited bone marrow leukopoicsis (S), and maintainctl in DBA/2 mitt by weekly transfers of 10^
<br /> I:olodny ct al. reported that marihuana stay impair ccllx derived from the pcriwneal cat•iq•. In these cxpcri•
<br /> ceaostermte secretion anti spermatogenesis. Purtherntore, meats, IUs Ieukentia cellx were inoculated ip uuo
<br />
<br /> • Xahas et al. (7) shoteed that in chronic marihuana users (C!i7li[./fi X DIl:1/2)Ft (IillF,) mice, and The mire were
<br /> there is a decreased I}•ng7hot}'te reactivity to mitogens as treated daily Ior 1D consecutive [lays heginning 2.1 hours
<br /> measured by thymidine uptake. 'These and other (3) after tumor cell inoculation. A[ean sun•itml tiara ryas
<br /> obscrcations suggest that ntarihu:ma (~":I IIC) interferes used as an index of drug activity.
<br /> frith vital cell biochemical processes, though no definite !rr vino calf t)vternr.-l,eteis Iwtg tumor: R'e obtained
<br /> mechanism has }'et been established. A preliminary re- isolated I,eteis lung rumor cells by subjecting 1-mni' sec•
<br /> port from this laboratory (9) indicated that the ability o[ lions of tumor to Q25 ; trypsin at 22° C anti stirring far
<br /> ~'•l'IIC to interfere with normal cell functimts might 00-90 winutes. After tr}'psiniration, the cells were ttntri•
<br /> prose e(ficacioas against neoplasms. This report repre•
<br /> tents an effort to tell various cuntabinoids in several , Reccirr,l Drcauber Re, 1971; acrepirJ It(ay 70, 1975.
<br /> in t'it'oantl in vitro punUr Sylletil5 to delenninC IItC aSuppe,nal by Public Healtb S<rrice gent UAOOIJO fmrn the
<br /> kinds of tumors that arc Seit9i live to 117CrC CUntlx)u ittla National Inrtiune on Drug Abux. Itcahh San i<o k M<nul
<br /> and reveal their possible biochemical sites of action(s), 11nhh AJnrini.tration: by a gran Irom the A1<aander and \la-
<br /> garcl Stee'art "rrurt Fund; and by an imtitutional grant from the
<br /> • Amrrinn Canc<r Society. •
<br /> MATERIALS AND METHODS a Drpanment or Pharmarolo~y anJ tlm AICY/PCU Canr<r Cen-
<br /> ter. M<di<al Coll<ge of t'irgiura, \'irgiuia Com mona~ea lih Unit<r•
<br /> 'lire tumor systems used wcrc the Lewis lung adcno• sity, Rldunond. va. zsrre.
<br /> LOUR CAI. OF TIIE NATIONAL CANCE0. INSTITUTE., VOL. 55. HO. Sr P'r r.alerR 1975 5~7
<br /> FIRf~• TtiIRfF PAGfS~ 4o~a? 1T4 3~~ 57
<br /> )rtb I<~ U S~
<br /> $et[. Ybt ~101enied ~
<br /> ~t, JUN l 61991
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