A.E. Munson, L.S. Harris, M.A. Friedman, W.L. Dewey, and R.A. Carchman
Journal of the National Cancer Institute, Vol. 55, No. 3, September 1975
Supported by Public Health Service grant DA00490 from the National Institute on Drug Abuse, Health Services & Mental Health Administration; by a grant from the Alexander and Margaret Stewart Trust Fund; and by an institutional grant from the American Cancer Society.
Department of Pharmacology and the MCV/VCU Cancer Center, Medical College of Virginia, Virginia Commonwealth University. Richmond, Va. 23298
Abstract
Lewis lung adenocarcinoma growth was retarded by the oral administration of delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta-9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta-8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta-9-THC, delta-8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg;, respectively), whereas CBD did not. Delta-9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 X DBA/2) F (BDF) mice hosting the L1210 murine leukemia. However, delta-9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta-8-THC and delta-9-THC showed a dose-dependent (10 -4 10 -7) inhibition (80-20%, respectively) of tritiated thymidine and 14C -uridine uptake into these cells. CBD was active only in high concentrations (10 -4)
Introduction
Investigations into the physiologic processes affected by the psychoactive constitutuents of marihuana [delta-9-tetrahydrocannabinol (delta-9-THC) and delta-8-tetrahydrocannabinol (delta-8-THC)] purified from Cannabis sativa are extensive (1). However, only recently have attempts been made to elucidate the biochemical basis for their cytotoxic or cytostatic activity. Leuchtenberger et al. (2) demonstrated that human lung cultures exposed to marihuana smoke showed alterations in DNA synthesis, with the appearance of anaphase bridges. Zimmerman and McClean (3), studying macromolecular synthesis in Tetrahymena, indicated that very low concentrations of delta-9-THC inhibited RNA, DNA, and protein synthesis and produced cytolysis. Stenchever et al. (4) showed an increase in the number of damaged or broken chromosomes in chronic users of marihuana. Delta-9-THC administered iv inhibited bone marrow leukopoieses (5), and Kolodny et al. (6) reported that marihuana; may impair testosterone secretion and spermatogenesis.
Furthermore, Nahas et al. (7) showed that in chronic marihuana users there is a decreased lymphocyte reactivity to mitogens as measured by thymidine uptake. These and other (8) observations suggest that marihuana (delta-9-THC) interferes with vital cell biochemical processes, though no definite mechanism has yet been established. A preliminary report from this laboratory (9) indicated that the ability of delta-9-THC to interfere with normal cell functions might prove efficacious against neoplasms. This report represents an effort to test various cannabinoids in several in vivo and in vitro tumor systems to determine the kinds of tumors that are sensitive to these compounds and reveal their possible biochemical sites of action(s).
