Safety and efficacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of high-grade glioma
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To test in vitro and in vivo the safety and efficacy of a novel chemotherapeutic agent, KM-233, for the treatment of glioma.
In vitro cell cytotoxicity assays were used to measure and compare the cytotoxic effects of KM-233, Δ8-tetrahydrocannabinol (THC), and bis-chloroethyl-nitrosurea (BCNU) against human U87 glioma cells. An organotypic brain slice culture model was used for safety and toxicity studies. A human glioma-SCID mouse side-pocket tumor model was used to test in vivo the safety and efficacy of KM-233 with intratumoral and intra-peritoneal administration.
KM-233 is a classical cannabinoid with good blood brain barrier penetration that possesses a selective affinity for the CB2 receptors relative to THC. KM-233 was as efficacious in its cytotoxicity against human U87 glioma as Δ8-tetrahydrocannabinol, and superior to the commonly used anti-glioma chemotherapeutic agent, BCNU. The cytotoxic effects of KM-233 against human glioma cells in vitro occur as early as two hours after administration, and dosing of KM-233 can be cycled without compromising cytotoxic efficacy and while improving safety. Cyclical dosing of KM-233 to treat U87 glioma in a SCID mouse xenograft side pocket model was effective at reducing the tumor burden with both systemic and intratumoral administration.
These studies provide both in vitro and in vivo evidence that KM-233 shows promising efficacy against human glioma cell lines in both in vitro and in vivo studies, minimal toxicity to healthy cultured brain tissue, and should be considered for definitive preclinical development in animal models of glioma.
Keywordsbrain tumor cannabinoid chemotherapeutic glioma therapy
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This work was supported by a research grant from the Methodist Foundation (Memphis, TN). The authors thank Mariya Nazarova and Dr. Xiaofei Wang for their excellent technical contribution to this work.
- 5.Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, Owens G, Ransohoff J II, Robertson JT, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA, 1980 Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery N Engl J Med 303:1323–1329PubMedCrossRefGoogle Scholar
- 8.Green SB, Byar DP, Walker MD, Pistenmaa DA, Alexander E Jr, Batzdorf U, Brooks WH, Hunt WE, Mealey J Jr, Odom GL, Paoletti P, Ransohoff J II, Robertson JT, Selker RG, Shapiro WR, Smith KR Jr, Wilson CB, Strike TA, 1983 Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma Cancer Treat Rep 67:121–132PubMedGoogle Scholar
- 10.Nelson DF, Diener-West M, Weinstein AS, Schoenfeld D, Nelson JS, Sause WT, Chang CH, Goodman R, Carabell S, 1986 A randomized comparison of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of malignant glioma after surgery: final report of an RTOG study Int J Radiat Oncol Biol Phys 12: 1793–1800PubMedGoogle Scholar
- 12.Grossman SA, O’Neill A, Grunnet M, 2000 Phase III study comparing three cycles of infusional BCNU/cisplatin followed by radiation with radiation and concurrent BCNU for patients with newly diagnosed supratentorial glioblastoma multiforme Proc Am Soc Clin Oncol 19: 158aGoogle Scholar
- 14.Levin VA, Maor MH, Thall PF, Yung WK, Bruner J, Sawaya R, Kyritsis AP, Leeds N, Woo S, Rodriguez L, et al., 1995 Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme Int J Radiat Oncol Biol Phys 33: 357–364PubMedCrossRefGoogle Scholar
- 15.Levin VA, Yung WK, Bruner J, Kyritsis A, Leeds N, Gleason MJ, Hess KR, Meyers CA, Ictech SA, Chang E, Maor MH, 2000 Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV for the treatment of anaplastic gliomas Neurooncol 2: 278Google Scholar
- 17.Halperin EC, Herndon J, Schold SC, Brown M, Vick N, Cairncross JG, Macdonald DR, Gaspar L, Fischer B, Dropcho E, Rosenfeld S, Morowitz R, Piepmeier J, Hait W, Byrne T, Salter M, Imperato J, Khandekar J, Paleologos N, Burger P, Bentel GC, Friedman A, 1996 A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain CNS. Cancer Consortium. Int J Radiat Oncol Biol Phys 34: 793–802PubMedCrossRefGoogle Scholar
- 18.Prados MD, Larson DA, Lamborn K, McDermott MW, Sneed PK, Wara WM, Chang SM, Mack EE, Krouwer HG, Chandler KL, Warnick RE, Davis RL, Rabbitt JE, Malec M, Levin VA, Gutin PH, Phillips TL, Wilson CB, 1998 Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors Int J Radiat Oncol Biol Phys 40:57–63PubMedCrossRefGoogle Scholar
- 19.Nelson DF, Diener-West M, Horton J, Chang CH, Schoenfeld D, Nelson JS, 1988 Combined modality approach to treatment of malignant gliomas – re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group NCI Monogr 6:279–284PubMedGoogle Scholar
- 20.Stupp R, Dietrich PY, Ostermann Kraljevic S, Pica A, Maillard I, Maeder P, Meuli R, Janzer R, Pizzolato G, Miralbell R, Porchet F, Regli L, de Tribolet N, Mirimanoff RO, Leyvraz S, 2002 Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide J Clin Oncol 20: 1375–1382PubMedCrossRefGoogle Scholar
- 26.Zhu W, Friedman H, Klein TW, 1998 Delta 9-tetrahydrocannabinol induces apoptosis in macrophages and lymphocytes: involvement of Bcl-2 and caspase-1 J Pharmacol ExpTher 286: 1103–1109Google Scholar
- 27.Melck D, De Petrocellis L, Orlando P, Bisogno T, Laezza C, Bifulco M, Di Marzo V, 2000 Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation Endocrinology 141: 118–126PubMedCrossRefGoogle Scholar
- 30.Fowler CJ, Jonsson KO, Andersson A, Juntunen J, Jarvinen T, Vandevoorde S, Lambert DM, Jerman JC, Smart D, 2003 Inhibition of C6 glioma cell proliferation by anandamide, 1-arachidonoylglycerol, and by a water soluble phosphate ester of anandamide: variability in response and involvement of arachidonic acid Biochem Pharmacol 66: 757–767PubMedCrossRefGoogle Scholar
- 40.Duntsch CD, Zhou Q, Jayakar HR, Weimar JD, Robertson JH, Pfeffer LM, Wang L, Xiang Z, Whitt MA, 2004 Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model J Neurosurg 100: 1049–1059PubMedGoogle Scholar
- 43.Rolhion C, Penault-Llorca F, Kemeny JL, Kwiatkowski F, Lemaire JJ, Chollet P, Finat-Duclos F, Verrelle P, 1999 O(6)-methylguanine-DNA methyltransferase gene (MGMT) expression in human glioblastomas in relation to patient characteristics and p53 accumulation Int J Cancer 84: 416–420PubMedCrossRefGoogle Scholar