| 1. |
- Gleissman, Helena, et al.
(författare)
-
Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo
- 2011
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 128:7, s. 1703-1711
-
Tidskriftsartikel (refereegranskat)abstract
- Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the Pediatric Preclinical Testing Program evaluation scheme used as a measurement of treatment response showed that untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response, depending on the DHA concentration. In conclusion, prophylactic treatment with DHA delayed neuroblastoma development, suggesting that DHA could be a potential agent in the treatment of minimal residual disease and should be considered for prevention in selected cases. Treatment results on established aggressive neuroblastoma tumors suggest further studies aiming at a clinical application in children with high-risk neuroblastoma.
|
|
| 2. |
|
|
| 3. |
- Ponthan, Frida, et al.
(författare)
-
Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo
- 2007
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:3, s. 1036-1044
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2- specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.
|
|
| 4. |
- Ponthan, Frida
(författare)
-
Retinoids in experimental neuroblastoma therapy
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Retinoids are analogues of vitamin A, with documented activity against various malignant cell types. Neuroblastoma is a childhood tumour of the sympathetic nervous system that shows a complex clinical and biological heterogeneity, often with poor outcome despite intensive multimodal therapy. The aim of the thesis was to investigate effects of retinoid treatment in vitro on human neuroblastoma cells, and in vivo on human neuroblastoma xenografts in nude rats. The ultimate goal was to find a new retinoid treatment for children with neuroblastoma. Oral treatment with 9-cis RA in vivo resulted in a significant inhibition of neuroblastoma tumour growth, but with major toxic side effects. Further experiments showed that 9-cis RA might not be suitable for clinical use in children with neuroblastoma, because of its short half-life, low bioavailability and toxic profile in rats. Ro 13-6307 was established to be a morphologically differentiating retinoid, able to reduce proliferation and induce GI growth arrest in both MYCN amplified and non-amplified neuroblastoma cell lines in vitro. Further experiments showed that oral Ro 13-6307 could inhibit neuroblastoma, tumour growth in vivo with limited toxicity. In vitro and in vivo results indicated that Ro 13-6307 was at least as effective as the clinically established retinoid 13-cis RA. These results demonstrate that Ro 13-6307 is a potential retinoid for clinical oral therapy of children with neuroblastoma. Despite promising results demonstrating that fenretinide induces apoptosis in neuroblastoma cells in vitro, no significant reduction in neuroblastoma tumour growth was observed after oral treatment with fenretinide in vivo. Five different doses were evaluated, but no significant inhibiting effect on tumour growth or morphological changes were found in treated compared to untreated tumours. Other alternatives for fenretinide administration should be investigated in future experimental and clinical studies. Proton magnetic resonance spectroscopy was found to be a suitable method for detecting metabolic alterations in neuroblastoma cells in vitro undergoing fenretinide-induced apoptosis. It was possible to monitor the kinetics in the treatment response and to distinguish between fenretinide-sensitive and -resistant cells. These findings suggest that proton magnetic resonance spectroscopy is a potential clinical non-invasive tool to monitor early tumour response to retinoid treatments. In conclusion, retinoids were shown to inhibit growth of human neuroblastoma cells in vitro and in vivo, however the effect depends on the retinoid in use. Dosing, scheduling, and toxicity are important factors determining the therapeutic efficacy of retinoids in vivo. Ro 13-6307 may be a retinoid for future clinical therapy of children with neuroblastoma.
|
|
| 5. |
- Träger, Chatarina, 1962-, et al.
(författare)
-
Quantitative analysis of tyrosine hydroxylase mrna for sensitive detection of neuroblastoma cells in blood and bone marrow
- 2003
-
Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 49:1, s. 104-112
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Sensitive monitoring of minimal residual disease may improve the treatment of neuroblastoma in children. To detect and monitor neuroblastoma cells in blood and bone marrow, we developed a quantitative method for the analysis of tyrosine hydroxylase mRNA. Methods: We used real-time reverse transcription-PCR. The calibrator was constructed from a segment of tyrosine hydroxylase mRNA that included the target. Blood and bone marrow samples from 24 children with neuroblastoma and 1 child with ganglioneuroma were analyzed. Controls were blood samples from the cords of 40 babies, from 58 children 6 months to 15 years of age, and from 34 healthy adults, as well as from 12 children with other diseases. Results: The detection limit was ~70 transcripts/mL. All 144 blood controls were below this limit. At diagnosis, blood tyrosine hydroxylase mRNA was higher in children with widespread disease (stage 4/4S, n = 6, range, 203-46 000 transcripts/mL) than in patients with localized disease (stages 1-3, n = 6, =83 transcripts/mL, P = 0.002). Bone marrow from all five children with localized disease had concentrations <72 transcripts/mL, whereas five of six stage 4 patients had increased concentrations (6000-8 000 000 transcripts/mL, P <0.05). In nine children in whom tyrosine hydroxylase mRNA was measured repeatedly, the results corresponded to the clinical course. Conclusion: Quantitative analysis of tyrosine hydroxylase mRNA in blood and bone marrow is reliable and easy to perform and may be used for upfront staging, prognostic assessment, and treatment monitoring of neuroblastoma.
|
|
| 6. |
- Wickström, Malin, et al.
(författare)
-
The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo
- 2007
-
Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:9, s. 2409-2417
-
Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is the most common extracranial solid tumor of childhood. The activity of J1 (l-melphalanyl-p-l-fluorophenylalanine ethyl ester), an enzymatically activated melphalan prodrug, was evaluated in neuroblastoma models in vitro and in vivo. Seven neuroblastoma cell lines with various levels of drug resistance were screened for cytotoxicity of J1 alone or in combination with standard cytotoxic drugs, using a fluorometric cytotoxicity assay. J1 displayed high cytotoxic activity in vitro against all neuroblastoma cell lines, with IC50 values in the submicromolar range, significantly more potent than melphalan. The cytotoxicity of J1, but not melphalan, could be significantly inhibited by the aminopeptidase inhibitor bestatin. J1 induced caspase-3 cleavage and apoptotic morphology, had additive effects in combination with doxorubicin, cyclophosphamide, carboplatin, and vincristine, and synergistically killed otherwise drug-resistant cells when combined with etoposide. Athymic rats and mice carrying neuroblastoma xenografts [SH-SY5Y, SK-N-BE(2)] were treated with equimolar doses of melphalan, J1, or no drug, and effects on tumor growth and tissue morphology were analyzed. Tumor growth in vivo was significantly inhibited by J1 compared with untreated controls. Compared with melphalan, J1 more effectively inhibited the growth of mice with SH-SY5Y xenografts, was associated with higher caspase-3 activation, fewer proliferating tumor cells, and significantly decreased mean vascular density. In conclusion, the melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.
|
|
