Brain tumours, effect of cannabinoids in animal models
| Disease model | Treatment | Comparator | Results | Ref. |
|---|---|---|---|---|
| 2 human medulloblastoma (D283, D425), intracranial xenografts, mice | Synthetic CBD 50 mg/kg i.p. or p.o.; 5 times a week, over 5 weeks | D283: THC 15 mg/kg; Combination: 50 mg CBD + 15 mg THC; D425: CBD 22.5 mg/kg; THC 45 mg/kg, or CBD + THC = 22.5 mg/kg + 22.5 mg/kg | CBD ≃ THC ≃ vehicle; No signif. change in survival compared to vehicle was observed with CBD, THC or THC + CBD combination in both xenografts; (D283 xenograft: THC 23 days, CBD 25 days, combination 21 days, vehicle 30 days); D425: neither THC nor CBD + THC improved survival; results were similar for i.p. and p.o. | [42] |
| 2 glioma (C6.9 or C6.4), s.c. xenografts; mouse, immuno-deficient | THC peri-tumoral, 0.5 mg/day for 8 days (~20 mg/kg) | Vehicle | THC decreases tumour volume and down-regulates MMP-2 expression of C6.9 by about 50% but not of C6.4 cells | [43] |
Neuro-blastoma cells (SK-N-SH), s.c. xenograft; Nonobese diabetic immuno-deficient NOD/SCID mice | Synthetic CBD 20 mg/kg per day i.p. for 14 days | THC 20 mg/kg per day i.p., or ethanol vehicle or untreated | CBD > THC; Response to treatment was better in the group with CBD; median xenograft volume at the end of treatment was 2.31 cm3 in the CBD-treated group compared with 3.46 cm3, (THC), 4.28 cm3 (untreated) and 4.31 cm3 in the vehicle-treated group | [44] |
| Glioma model (C6 cells), intracerebral implanted; rats (250—300 g b.w.) | THC intra-tumoral, total dose 2.5 mg/rat over 7 days (~1.5–2 mg/kg THC per day) | WIN-55,212-2 0.25 mg/kg (synthetic cannabinoid similar to THC) | THC was ineffective in 3/15 rats, but tumour was completely eradicated in 3/15 rats, survival prolonged in 9 rats (up to 19–35 days vs. controls 12–18 days); WIN-55,212-2 was roughly similarly effective in the prolongation of survival (ineffective in 6, complete eradication of tumours in 5 rats) | [45] |
| Human glioblastoma (U87MG cells), orthotopic xenograft, nude mice | CBD 15 mg/kg i.p. per day for 21 days | TMZ 25 mg/kg per day; CBD + TMZ, for 21 days | 50% survival: CBD + TMZ ~60 days, TMZ ~52 days, CBD ~50 days, vs. control ~42 days; 0% survival: CBD + TMZ 84 days, TMZ 60 days, CBD 55 days, vs. control 50 days | [46] |
| Human glioma (U87MG), heterotopic s.c. xenografts, nude mice | Synthetic CBD 15 mg/kg p.o. per day for 15 days | TMZ 5 mg/kg i.p. twice weekly; CBD + TMZ, or vehicle | Tumour volume TMZ < CBD + TMZ < CBD (~30% lower with CBD, ~70% lower with TMZ and ~50% lower with CBD + TMZ compared to controls); no enhancement of anticancer activity by combination CBD + TMZ | [47] |
| Glioma (U87MG), s.c. xenografts, nude mice | CBD, THC (extracts) p.o. daily for 15 days | Ratio THC:CBD = 1:1 or 1:4 (5 mg/kg p.o. each or THC 6.5 mg/kg + CBD 24.5 mg/kg, TMZ 5 mg/kg i.p. | THC + CBD at a 1:4 ratio resulted in a marginally lower tumour size than the 1:1 combination (but still higher than TMZ, as determined by MRI; combination with TMZ increased survival, a higher ratio of CBD had no effect | [47] |
| Glioma (U87MG), s.c. xenografts, nude mice | CBD, THC (extracts) p.o. daily for 15 days | CBD + THC + TMZ (ratio THC:CBD = 1:1, 1:4, 1:6); 3.5 mg/kg p.o. each or THC 4.5 mg/kg + CBD 16.5 mg/kg or THC 5.2 mg/kg + CBD 29.5 mg/kg); TMZ 5 mg/kg i.p. | All CBD + THC combinations inhibit tumour growth to a very similar extent but less than TMZ alone; effect was enhanced by the combination with TMZ with no relevant difference between 1:1, 1:4 and 1:6 ratio of THC:CBD | [47] |
| Orthotopic intracranial glioma xenografts U87MG, nude mice | CBD, THC (extracts) p.o. daily for 15 days | CBD + THC + TMZ; THC + CBD (1:4); THC 6.5 mg/kg + CBD 24.5 mg/kg; TMZ 5 mg/kg i.p. | Administration of THC + CBD at a 1:4 ratio did not affect tumour size significantly (as determined by MRI) and did not increase survival in contrast to TMZ; the combination with TMZ decreased tumour growth and increased survival significantly from ~30 (control) to > 50 days | [47] |
| Orthotopic intracranial xenografts, 12O12 GICs, nude mice | Synthetic CBD, synthetic THC p.o. | THC + CBD (1:1 or 1:5) 5 mg/kg each or THC 5 mg/kg p.o. + CBD 25 mg/kg daily for 14 days, then 3 times a week for further 2 weeks; TMZ (5 mg/kg i.p. twice a week); CBD + THC + TMZ | TMZ + THC + CBD (1:5) was most effective in reducing tumour growth (MRI) and increasing survival; THC:CBD (1:1) was less effective than 1:5, and less effective than TMZ alone; a combination (THC:CBD 1:1 or 1:5) with TMZ increased these effects; Pure single CBD or THC was not included | [47] |
| Human glioblastoma (U87 cells), s.c. xenograft, athymic nude mice | CBD 0.5 mg/mouse (i.e., ~25 mg/kg per day, 5 days/week, 23 days | (vs. control) | Tumours of animals treated with CBD were significantly smaller; day 18, 572 mm3 (control 1,765 mm3); day 23, 1,210 mm3 (control 2,212 mm3) | [48] |
| Patient-derived DIPGXIIIP cells orthotopically implanted into the brainstem of immunodeficient mice | CBD 15 mg/kg 5 days per week until morbidity of all control mice | Vehicle | Significantly longer survival with CBD 15 mg/kg (median 58 days vs. 49 days); CBD inhibited ID-1 expression | [49] |
| Mouse glioma (GL261 cells), orthotopically implanted, mice | CBD-E, THC-E | CBD-E + THC-E (each ~2 mg/kg on day 9, 13, and 16 after tumour implantation; followed by X-ray irradiation (4 Gy) on day 9 | > 85% decrease of tumour volume and of vascularisation on day 21 (animals sacrificed); combination of CBD-E + THC-E reduced progression, further enhanced by irradiation 4 h after drug administration (stagnant tumour sizes throughout the experiment); X-rays alone had no dramatic effects; pure CBD or THC were not included | [50] |
| 2 intracranial glioma stem cell xenografts (3832 and 387 GSC cell lines); female athymic nu/nu mice | CBD 15 mg/kg i.p., 5 times a week for ~25 days after tumour induction | (vs. control) | CBD inhibited tumour growth and improved significantly the survival of mice bearing intracranial glioma initially but tumour resistance was observed later on; median survival with CBD in 3832 was 33 days and in 387 GSC cell lines 26 days; compared to 27 and 21 resp. (controls) | [51] |
| Glioblastoma (U251 cells), orthotopic intracranial xenograft, mice | CBD 15 mg/kg i.p., 5 days per week for 28 days | (vs. control) | Signif. (~95%) decrease of tumour area; in 1/5 mice treated no tumour cells were observed in any of the brain regions analysed | [52] |
| Glioblastoma (U251 cells), s.c. xenograft, mice | CBD 20 mg/kg i.p., 5 days per week for 48 days | (vs. control) | A similar dose-dependent effect was observed in a s.c. model and with peritumoral injection of CBD; the tumour volume was ~30% lower with 15 mg/kg and ~50% lower with 20 mg/kg; CBD eradicated the tumour in 1 of 5 animals | [52] |
| 2 human glioma cell lines (U87MG or T98G), s.c. xenograft, nude mice | CBD 7.5 mg/kg per day; Peri-tumoral injection, 14 days; (15 mg/kg not tested) | THC 7.5 mg/kg per day or THC 15 mg/kg or CBD + THC each 7.5 mg/kg per day or a nabiximols-like preparation (15 mg/kg per day) | CBD ≃ THC (7.5 mg/kg per day); Effect of a submaximal dose of 7.5 mg/kg THC increased when combined with CBD 7.5 mg/kg per day; THC + CBD (each 7.5 mg/kg) ≃ 15 mg/kg THC; a nabiximols-like combination of extracts reduced the growth of U87MG tumour xenografts to the same extent as an identical dose of pure THC | [53] |
CBD-E: CBD-extract (synonym: CBD-BDS, CBD botanical drug substance); THC-E: THC-rich extract; GICs: glioma-initiating cells (supposed to be responsible for treatment relapse); i.p.: intraperitoneal injection; MRI: magnetic resonance imaging; signif.: significant; p.o.: per os; b.w.: body weight; resp.: respectively; s.c.: subcutaneous injection; ≃: almost equal; ~: about
