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Antineoplastic Activity c0clinnabinolds' ' O
<br />A. E. Munson, L. S. Harris, M. A. Friedman, W. L. Dewey, and R. A. Carchman 3
<br />SUMMARY—Lewis lung adenocarclnoms growth was retarded
<br />by the oral administration of Ar -tetrahydrocannabinol (Ar -THC),
<br />A` -tetrahydrocannabinol (A' -THC), and cannabinol (CBN), but
<br />not cannabidiol (CBD). Animals treated for 30 consecutive days
<br />with A' -THC, beginning the day after tumor Implantation,
<br />demonstrated a dose-dependent action of retarded tumor
<br />growth, Mice treated for 20 consecutive days with As -THC and
<br />CON had reduced primary tumor size. CBD showed no Inhlbl•
<br />tory effect on tumor growth at 14, 21, or 28 days. A' -THC,
<br />A' -THC, and CON Increased the mean survival time (36% at
<br />100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, re•
<br />spectively), whereas CBD did not. .11 -THC administered orally
<br />dally until death In doses of 50, 100, or 200 mg/kg did not
<br />Increase the life -spans of (C578L/6 x DBA/2)Fl (BDF,) mice
<br />hosting the L1210 murine leukemia. However, As -THC admin-
<br />Istered dally for 30 days significantly Inhibited Friend leu.
<br />kemia virus -Induced splenomegaly by 71% at 200 mg/kg as
<br />compared to 90.2% for actinomycin D. Experiments with bone
<br />marrow and Isolated Lewis lung cells Incubated In vitro with
<br />AP -THC and Aa -THC showed a dose-dependent (10.1-10,1)
<br />Inhibition (80-20%, respectively) of titillated thymidine and
<br />11C.uridine uptake Into these cells. CBD was active only In
<br />high concentrations (10-1),—) Nall Cancer Inst 55: 597-602,
<br />1975.
<br />Investigations into the physiologic processes affected
<br />by file psychoactive constituents of marihuana fpr-tetra-
<br />Ipdrocannabinol (A'-TFIC) and A'.tctrahydroc-innabinol
<br />(Y.TIIC)j purified from Cannabis sntiva are extensive
<br />(1). l to vever, only recently have aaseuspts been made to
<br />elucf(bae the biochemical basis for their cytotoxic or,
<br />cytostatic activity. Lcuchfcnbciger ct al. (2) demon.
<br />strated that human lung culhtcs exposed to marihuana
<br />smoke showed alterations in DNA synthesis, scull the
<br />appealance of anaphase bridge%. 7.inunernil" 111d Afc-
<br />Clean ()), s(ildying macromolecular synthesis in Tc7in-
<br />hynrenn, indicated shit VCly IOIv coriceintr.1tioil% of 69.
<br />TIM inhibited RNA, DNA, and plotein synthesis alld
<br />produced c tolysis. Stenchever et a). (1) showed an in-
<br />a'case in the number of damaged or broken chromo-
<br />somes in chronic users of marihuan-i. As-7'IIC adminis-
<br />tered iv inhibited bone marrow Icukopoicsis (3), and
<br />KOlodny et al. (0) reported that marihuana may impair
<br />a
<br />scostcrouc secretion -incl spermatogenesis. Fursherniore,
<br />Nahas et al. (7) showed that in chronic marihuana users
<br />dleie is a decrease(] IyrnphocJ'te reactivity to mitogens as
<br />measured by thymidine uptake. These and other (8)
<br />observations suggcsf that marihuana (;1':I-IIC) interferes
<br />with s•it'll cell biocllentical processes, though no definite
<br />nicchani.snt has yet been esmblishcd. A preliminary re.
<br />POI -1 hon this laboratory (9) indicated that file ability of
<br />-%'--I'IIC to interfere with normal cell functions might
<br />prove efficacious against neoplasms. -Fhis report repre-
<br />sents an effort to test various cannabinoids in several
<br />in vivo and in vitro Unnor systems to determine the
<br />kinds of tumors that arc sensitive to Thcsc coollsoanlds
<br />and reveal their possible biochemical sites of action(s).
<br />MATERIALS AND METHODS
<br />The tumor systems used sverc the Lcwis lung adcno-
<br />k-r
<br />carcinoma, leukemia L1210, and B -tropic Friend leu-
<br />kemia.
<br />!n vivo spslcnis.-1-CIvis Will; tumor; For the mainte-
<br />nance of file "wets lung carcinoma, approximately
<br />1 -mm' pieces of tunior were transplanted into C57BL/6
<br />mice wall a 15 -gauge trocar. !n experiments involving
<br />chemotherapy, 14- to 18 -day-old tumors were excised,
<br />cleared of (debris and necrotic tissue, and cut into small
<br />fragments (== I nima). Tumor tissue was tile,, placed in
<br />0.25;, trypsin in Dulbecco's medium with 100 U penicil-
<br />"11/1111 and 100 pg streptomycin/ml. After 90 minutes'
<br />incubation at 22° C. trypsin action leas stopped by file
<br />ad(lition of complete mediuni containing heat-inacti.
<br />entad fetal calf serum (final concentration, 20;). Cells
<br />sverc washed two tinges in complete medium, entnnerated
<br />in a Cot ]it
<br />counfcr (Model Z13,) or on a hcmocytometcr,
<br />and resilsperl(lc(I in serum -free medium at a concentra-
<br />liou of 5x 104 cells/nil. Next I x 104 cells were injected
<br />fun into the right hind gluteus muscle, and (]rugs admin.
<br />isicred as described in "Results." Standard regimens pro.
<br />vided for 10 consecutive (gaily doses beginning 21 hours
<br />after tumor inoculation. Body weights were recorded be.
<br />fore tumor inoculation -incl weekly for 2 weeks. Tumor
<br />si7c was measured weekly for the duration of the cx(,cri-
<br />ment and converted to mg tumor weight, as described
<br />by Mayo (/0).
<br />Friend leukemia: B -tropic Friend leukemia ,virus
<br />(FIA') was maintained in IIAI,B/c "lice, and dnlg evalu-
<br />ation performed in the sante animals. Pools of virus wcic
<br />plep-ired floor like plasma of mice given FLV and stored
<br />at -700 C. In cxperinients with FLV, 0.2 nil of a 1/20
<br />dilution of plasma (derive(] from FI,V.infected mice) in
<br />medium seas inoctllated if) into BA1.11/e mica Cannabi-
<br />noids sverc administered orally daily for 10 consecu.
<br />tive da)s beginning 2.1 hours after virus inoculation.
<br />T%venf)'-four hours after the last drug administration, the
<br />mice wcrc killed by cervical dislocation, and the spleens
<br />removed and svcigllcd. \rice not given FLV wcrc treated
<br />as described above, to e%•aluate possible drag induced
<br />spleuomcgaly.
<br />1.1210 leukemia: The murine leukemia L1210 was
<br />nrlinlained in DBA/2 mice by w'eckly transfers of 101
<br />cells derived from the peritoneal cavity. In these experi-
<br />orenss. IOa leukemia cells sverc inoculated ill into
<br />(C57ISI./6 X DBA/2)17, (IIDF,) mice, and the ,,)ice sverc
<br />treated (gaily for 10 consecutive (la)s beginning 21 hours
<br />after tunsor cell inoculation. Mean survival time %vas
<br />used as an index of drug activity.
<br />!n villa c"fl J)slerns.—Lewis lung tumor: We obtained
<br />isolated I.e%vis lung tumor cells by subjecting I-mrns sec-
<br />tions of utmor to 0.25:. trypsin at 220 C and stirring for
<br />60-90 minutes. After tr)psinization, the cells were centri-
<br />1 Recci%ed December 26, 1974; accepted pfay 30, 1975.
<br />'Supported by Public Ifeallh Senicc grant DA00190 frnin the
<br />\3(101131 tnrtitu(t on Drug Abuse. Ilcalth Scniccs k kfnnal
<br />Ilcalth Adruinirtntion; by a gnat from the Alexander and \lar
<br />garc( stcaart 'fruit Fun(; and by an imtilulional grant from lbe
<br />Anierican Cancer Society.
<br />a Deparlinent or rhatmacology and the klCl'/l'CU Cancer Cen.
<br />ler, Stedical C0IIc9e of Virginia. Virgil li3 ICV/VCU Can er Cen.
<br />III)', Ridwlond, Va. 23298,
<br />JOURNAL OF TIIE NATIONAL CANCER INSTITUTE, VOL, 53, NO. S, SF.r'r F.%IRER 1975
<br />Fitz FT TtilstF( PgGFS)
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