isotretinoin and Brain-Neoplasms

Biologic response modifiers are becoming an important addition to surgery, chemotherapy, and radiotherapy in the management of cancer. As this field of research grows and expands, more biologic response modifiers will be incorporated into therapeutic regimens. By stimulating the immune system to eradicate minimal residual disease, these agents may improve the disease-free and long-term survival rates of patients with a variety of malignancies. The challenge is to incorporate biologic response modifiers into the treatment armamentarium in ways that will maximize their tumorigenicity.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Child, Preschool; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cytokines; Drug Design; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Immunotherapy; Infant; Interleukins; Isotretinoin; Liposomes; Neoplasms; Neuroblastoma; Osteosarcoma; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylglycerols; Salvage Therapy; Sarcoma, Ewing

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Brain Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Contraindications; Cranial Irradiation; Craniotomy; Dacarbazine; Disease Progression; Epidemiologic Methods; Glioblastoma; Humans; Isotretinoin; Lomustine; Palliative Care; Procarbazine; Radiosurgery; Radiotherapy, Adjuvant; Radiotherapy, Conformal; Temozolomide; Treatment Outcome; Vincristine

Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.. PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array.. Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6).. It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cerebellar Neoplasms; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Humans; Infant; Isotretinoin; Male; Medulloblastoma; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Prospective Studies; Vincristine; Vorinostat

Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy.. The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide.. The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia.. The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma.. NCT00112502.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Brain Neoplasms; Celecoxib; Chemotherapy, Adjuvant; Dacarbazine; Disease-Free Survival; Drug Combinations; Female; Glioblastoma; Humans; Isotretinoin; Kaplan-Meier Estimate; Male; Middle Aged; Pyrazoles; Sulfonamides; Temozolomide; Thalidomide; Young Adult

Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM.. Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m(2) days 1 to 7 and 15 to 21) or metronomic (50 mg/m(2) continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status.. Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm).. Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemotherapy, Adjuvant; Dacarbazine; Disease Progression; Drug Administration Schedule; Female; Glioblastoma; Humans; Isotretinoin; Kaplan-Meier Estimate; Magnetic Resonance Imaging; Male; Middle Aged; Prospective Studies; Radiotherapy, Adjuvant; Temozolomide; Treatment Outcome

In a phase II clinical trial, we sought to determine if combining celecoxib with 13-cis-retinoic acid (13-cRA, Accutane) was efficacious in the treatment of recurrent (progressive) glioblastoma multiforme (GBM). In parallel, we also sought to determine to what extent the outcomes from this clinical trial correlated with the findings from studies utilizing two murine intracerebral GBM models, U87MG and U251HF, to determine the predictive value of these murine models. In the clinical trial, 25 patients were studied at recurrence. Stable disease, which occurred in 44% of the patients, was the best response. The median progression-free survival (PFS) was 8 weeks, with a PFS at 6 months of only 19%. For the patients with stable disease, the median PFS was 24 weeks. The toxicity profile was unremarkable. The modest effect on PFS seen in this study agreed with the recent findings of another study, which showed a 19% PFS at 6 months in patients treated with 13-cRA alone. Thus, the combination of 13-cRA with celecoxib is not more effective than 13-cRA in the treatment of progressive GBM. In the murine model study, we found that long-term dosing with 13-cRA or celecoxib alone or in combination did not increase survival in animals with U87MG tumors but modestly increased survival in animals with U251HF tumors. There was no evidence of synergism between the two drugs. From this, we concluded that the animal studies generally predicted that the two agents would have only a modest effect alone and no additive effect when given in combination to patients.

Topics: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Celecoxib; Disease Models, Animal; Disease-Free Survival; Female; Glioblastoma; Humans; Isotretinoin; Male; Mice; Mice, Nude; Middle Aged; Pyrazoles; Sensitivity and Specificity; Sulfonamides; Survival Analysis

Approximately 5% of patients with malignant glioma achieve complete response (CR) after first-line combined modality treatment. Although these patients will invariably suffer from tumor recurrence, they usually do not receive any further treatment to maintain remission. According to in vitro and in vivo clinical studies, 13-cis retinoic acid (cRA) may be a promising agent for maintenance therapy in these patients.. We initiated a clinical study to evaluate the feasibility and toxicity of high-dose cRA as maintenance therapy in patients with high-grade glioma in complete remission after first-line multimodal treatment.. A prospective single-arm phase-II study in patients with CR after combined first-line therapy (neurosurgery, radio- and chemotherapy) was performed. Patients were treated with cRA at 60 mg/m2 BS from day 1 to 21 in four-weekly cycles with a dose escalation of up to 100 mg/m2 BS until tumor recurrence. Clinical controls were performed every 4 weeks, magnetic resonance imaging every 8 weeks.. Twenty-three patients (10, grade IV; 13, grade III) were evaluable using an intention-to-treat analysis. Treatment was well tolerated for up to 149 weeks with moderate dermatological symptoms in all patients. No grade 4 toxicities were observed. Median time to progression was 41 weeks, median overall survival 74 weeks after inclusion in the protocol.. There is an urgent need for strategies maintaining remission in patients with malignant glioma. Maintenance therapy with high-dose cRA is feasible and well tolerated over long periods of time. A controlled clinical trial to test the efficacy of cRA as a maintenance treatment in malignant glioma is warranted.

Topics: Adult; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Disease Progression; Feasibility Studies; Female; Glioma; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Radiotherapy; Salvage Therapy; Survival Rate; Treatment Outcome

Interferon-alpha (IFN-alpha) has been safely given concurrently with radiation therapy (RT) in treating gliomas. As single agents, both IFN-alpha and cis-retinoic acid (CRA) have produced objective tumor regressions in patients with recurrent gliomas. In vitro, IFN-alpha2a and CRA enhance radiation therapy effects on glioblastoma cells more than either agent alone. This trial was conducted to determine the clinical effects of IFN-alpha2a and CRA when given concurrently with radiation therapy to patients with high-grade glioma. Newly diagnosed patients with high-grade glioma received IFN-alpha2a at a dosage of 3 to 6 million IU s.c. 4 times a day for 3 days per week and 1 mg/kg CRA by mouth 4 times a day for 5 days per week during the delivery of partial brain radiation therapy at 180 cGy x 33 fractions for 5 days per week for a total of 59.4 Gy during the 7-week period. Use of the antiepileptic phenytoin was prohibited after observing that the combination of IFN-alpha2a, CRA, and phenytoin was associated with a high rate of dermatologic toxicity not seen in a previous study with concurrent IFN-alpha2a and radiation therapy. Forty patients (26 men and 14 women) with a median age of 60 (range, 19 to 81 years) were enrolled between August 1996 and October 1998. Histopathologic diagnoses were glioblastoma multiforme or grade 4 anaplastic astrocytoma in 36 patients, and grade 3 anaplastic astrocytoma in 4 patients. Only 4 patients (10%) underwent a gross total resection of tumor prior to this therapy; 50% were asymptomatic when treatment was initiated. The planned 7-week course of concurrent therapy was completed by 75% of patients; 30% completed the 16-week course of IFN-alpha and CRA alone. At a median follow-up of 36 months, there were 37 deaths, with a median overall survival of 9.3 months and a 1-year survival rate of 42%. There was no improvement in survival compared with a similar group of 19 patients treated with concurrent IFN-alpha2a and radiation therapy in a previous trial. In the high-risk group of patients in the present study, concurrent treatment with IFN-alpha2a, CRA, and RT was feasible, but was not associated with a better outcome compared with a similar patient population treated with radiation therapy and IFN-alpha2a, or compared with radiation therapy alone in other trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brain Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Contraindications; Craniotomy; Drug Eruptions; Female; Glioblastoma; Humans; Hypertriglyceridemia; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Isotretinoin; Life Tables; Male; Middle Aged; Phenytoin; Radiation Injuries; Radioisotope Teletherapy; Recombinant Proteins; Survival Analysis; Treatment Failure

Malignant gliomas account for more than 60% of all primary brain tumors in adults. Adjuvant chemotherapy in addition to radical surgery and radiation therapy has provided only a modest increase in survival. Retinoic acid has been shown to have growth-inhibitory activity against glioma cells in culture. This provides the rationale for a Phase II study using 13-cis-retinoic acid (CRA) in patients with recurrent malignant brain tumors. The objective of this study was to determine the clinical activity of CRA in patients with a histologically proven diagnosis of malignant brain tumor and documented progressive or recurrent disease after radiation and chemotherapy. Fifty patients with documented recurrent disease were treated with CRA as a single agent p.o. at a dose of 60-100 mg/m2 per day. Three weeks of treatment were followed by 1 week of rest. Of the 43 patients who received more than 4 weeks of therapy, 3 (7%) achieved partial response, 7 (16%) achieved minor response, 13 (30%) remained stable, and 20 (47%) had disease progression. The median time from onset of treatment to disease progression for the whole group of 43 patients was 16 weeks (19 weeks for glioblastomas and 11 weeks for anaplastic glioma), whereas that for the 23 patients with partial response and minor response and who remained stable was 66 weeks, and that for the 20 patients with progressive disease was only 8 weeks. The median survival time for glioblastoma was 58 weeks, and 34 weeks for anaplastic astrocytoma. Toxicity was mainly dermatological, with dry skin and cheilitis. These preliminary results suggest that 13-cis-retinoic acid is active against malignant gliomas and is very well tolerated.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Disease Progression; ErbB Receptors; Female; Glioma; Humans; Isotretinoin; Male; Middle Aged; Neoplasm Recurrence, Local; Phosphorylation; Survival Analysis; Time Factors; Treatment Outcome

Topics: Brain Neoplasms; Child; Child, Preschool; Feasibility Studies; Humans; Infant; Isotretinoin; Vorinostat

Embryonal tumor with multilayered rosettes is a rare and highly malignant early childhood brain tumor. We report a case of embryonal tumor with multilayered rosettes in the parietooccipital region of a 2-year-old girl. Histopathology of the tumor demonstrated amplification of the 19q13.42 locus and strong positivity for LIN28A. Treatment was multimodal and included 3 surgical resections, adjuvant chemotherapy with autologous stem cell rescue, and focal radiotherapy. The use of the agents vorinostat and isotretinoin, and the addition of focal radiation have not been extensively described in this patient population, but may attribute to our patient's sustained remission at 2.5-years follow-up.

Topics: Autografts; Brain Neoplasms; Chemoradiotherapy, Adjuvant; Child, Preschool; Chromosomes, Human, Pair 19; Female; Genetic Loci; Humans; Isotretinoin; Neoplasms, Germ Cell and Embryonal; Stem Cell Transplantation; Vorinostat

To compare the pharmacokinetics of 13-cis retinoic acid (13-cisRA) between Indian and UK neuroblastoma patients receiving comparable treatment, alongside measures of toxicity and response.. 13-cisRA (160 mg/m(2)/day) was administered to 36 patients ≤16 years in two divided doses. Plasma 13-cisRA concentrations were determined on days 1 and 14 of cycles 1 and 4 of treatment. Area under the plasma concentration-time curve (AUC0-6h) was estimated using non-compartment modelling. Patients were genotyped for UGT2B7, CYP3A5*3, CYP3A7*2 and *2, *3 and *4 variants of CYP2C8.. Marked inter-patient variability in 13-cisRA pharmacokinetics was observed. There was a trend towards a higher AUC0-6h on day 1 versus day 14 for both treatment cycles studied. Children who swallowed 13-cisRA capsules (n = 18) achieved higher AUC0-6h values compared to those who could not (n = 16) (Mean AUC 21.53 vs. 9.35 µM h, P < 0.05). Patients who were event free at 1 year tended to have higher AUC0-6h on C1D1 compared to those patients who progressed, although this did not reach significance with the number of patients studied (P = 0.08). Similarly, patients who achieved a 13-cisRA C max of ≥2 µM on C1D1 tended to have higher median EFS compared to those who did not (17.0 vs. 8.1 months). UGT2B7, CYP2C8*2/*3/*4 or CYP3A5*3 genotype did not have any effect on 13-cisRA pharmacokinetics.. Method of administration markedly affects 13-cisRA pharmacokinetics in Indian neuroblastoma patients, supporting similar findings in UK patients. An appropriate oral liquid formulation of 13-cisRA that can be administered to all children with neuroblastoma is urgently needed on an international level.

Topics: Adolescent; Antineoplastic Agents; Area Under Curve; Brain Neoplasms; Child; Child, Preschool; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Drug Compounding; Female; Genotype; Glucuronosyltransferase; Humans; India; Infant; Isotretinoin; Male; Neuroblastoma; Pharmacogenetics; Risk Factors; Survival Analysis; Treatment Outcome; United Kingdom

Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Dacarbazine; Female; Glioblastoma; Humans; Isotretinoin; Male; Pyrazoles; Sulfonamides; Thalidomide

Glioblastoma multiforme and anaplastic astrocytoma are challenges to clinical biologists at present. The patients with glioblastoma have median survival of less than 12 months, despite advances in radiotherapeutical, chemotherapeutical and conventional surgical modalities. Retinoic acids are known to effect in vitro proliferation, differentiation, and apoptosis in colon, prostate, lung, and leukemia cancers. Retinoids are known to have anti-proliferation, anti-migration, and anti-invasive activity against human malignant gliomas, suggesting that retinoids are suitable anticancer agents to inhibit progression of tumors. Recurrent malignant cerebral gliomas have been treated with ATRA and 13-cis RA. However, the side effects associated with the use of high doses of retinoic acid demand for some more potent derivative free from such effects. The present clinical trials are undertaken to investigate the clinical safety and possible efficacy of administering retinoic acid naphthalene triazole (RANT) to patients with recurrent malignant gliomas. The toxicities observed in the patients during RANT treatment were mild. These preliminary results suggest that RANT is more potent compared to RA against recurrent malignant gliomas.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Dose-Response Relationship, Drug; Female; Glioma; Humans; Isotretinoin; Magnetic Resonance Imaging; Male; Middle Aged; Naphthalenes; Survival Analysis; Treatment Outcome

We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol.. From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs.. After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, (123)I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival.. mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Brain Neoplasms; Carboplatin; Child; Child, Preschool; Cisplatin; Cohort Studies; Consolidation Chemotherapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Female; Humans; Immunotherapy; Induction Chemotherapy; Infant; Isotretinoin; Male; Neoadjuvant Therapy; Neoplasm Staging; Neuroblastoma; Neurosurgical Procedures; Pilot Projects; Prospective Studies; Radiotherapy; Thiotepa; Topotecan; Treatment Outcome; Vincristine

The cell differentiation potential of 13-cis retinoic acid (RA) has not succeeded in the clinical treatment of glioblastoma (GBM) so far. However, RA may also induce the expression of resistance genes such as HOXB7 which can be suppressed by Thalidomide (THAL). Therefore, we tested if combined treatment with RA+THAL may inhibit growth of glioblastoma in vivo. Treatment with RA+THAL but not RA or THAL alone significantly inhibited tumour growth. The synergistic effect of RA and THAL was corroborated by the effect on proliferation of glioblastoma cell lines in vitro. HOXB7 was not upregulated but microarray analysis validated by real-time PCR identified four potential resistance genes (IL-8, HILDPA, IGFBPA, and ANGPTL4) whose upregulation by RA was suppressed by THAL. Furthermore, genes coding for small nucleolar RNAs (snoRNA) were identified as a target for RA for the first time, and their upregulation was maintained after combined treatment. Pathway analysis showed upregulation of the Ribosome pathway and downregulation of pathways associated with proliferation and inflammation. In conclusion, combined treatment with RA + THAL delayed growth of GBM xenografts and suppressed putative resistance genes associated with hypoxia and angiogenesis. This encourages further pre-clinical and clinical studies of this drug combination in GBM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Computational Biology; Databases, Genetic; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Humans; Isotretinoin; Mice, Nude; RNA, Small Nucleolar; Signal Transduction; Thalidomide; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma.. In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.. The median (range) IC(50) of single-agent CEP-701 across all cell lines was 0.09 (0.08-0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC(50) 1.5-fold (1.1-2.8-fold) and 1.7-fold (1.5-1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED(50) of 1.3 (1.1-1.5).. The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.

Topics: Antineoplastic Agents; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Drug Evaluation, Preclinical; Fenretinide; Furans; Humans; Isotretinoin; Neuroblastoma; Receptor, trkB

We hypothesized that induction of differentiation with retinoid could increase sensitivity to microtubule-binding drug taxol (TXL) for apoptosis in human glioblastoma T98G and U87MG cells. Treatment of cells with 1 microM all-trans retinoic acid (ATRA) or 1 microM 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation, overexpression of glial fibrillary acidic protein (GFAP), and also down regulated telomerase expression and activity, thereby increased sensitivity to TXL for apoptosis. Treatment of glioblastoma cells with TXL triggered production of reactive oxygen species (ROS), induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and activated the redox-sensitive c-Jun NH(2)-terminal kinase 1 (JNK1) pathway. Moreover, TXL activated Raf-1 kinase for phosphorylation and inactivation of anti-apoptotic Bcl-2 protein. The events of apoptosis included increase in expression of Bax, down regulation of Bcl-2 and baculoviral inhibitor-of-apoptosis protein (IAP) repeat containing (BIRC) proteins, mitochondrial release of cytochrome c and Smac into the cytosol, increase in intracellular free [Ca(2+)], and activation of calpain, caspase-9, and caspase-3. Increased activity of caspase-3 cleaved inhibitor of caspase-activated DNase (ICAD) to release and translocate CAD to the nucleus for DNA fragmentation. Involvement of stress signaling kinases and proteolytic activities of calpain and caspase-3 in apoptosis was confirmed by pretreating cells with specific inhibitors. Taken together, our results suggested that retinoid (ATRA or 13-CRA) induced astrocytic differentiation with down regulation of telomerase activity to increase sensitivity to TXL to enhance apoptosis in glioblastoma cells. Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Astrocytes; Blotting, Western; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Down-Regulation; Glioblastoma; Humans; Isotretinoin; Paclitaxel; Reactive Oxygen Species; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Telomerase; Tretinoin

Basic science and clinical investigations have demonstrated that 13-cis-retinoic acid (cRA) has activity against malignant gliomas. To assess its effectiveness in the setting of recurrent glioblastoma multiforme (GBM), we performed a retrospective analysis of the medical records and neuroimaging results of patients with recurrent GBM who were treated with cRA. The toxicity profile of cRA, response, and effect on progression-free survival from initiation of treatment were end points of our analysis. Eighty-two of 85 patients with a median age of 51 years received at least 1 full cycle of cRA. At the initiation of cRA treatment, the median Karnofsky performance score was 80. All patients had failed conventional radiotherapy. Seven patients were chemonaïve, whereas 75 patients had received some form of chemotherapy. Radiographic partial responses, minor responses, and stable disease were seen in 4%, 8%, and 34% of patients, respectively. Two patients were not assessable. Progression-free survival and overall survival after initiation of cRA were 10.0 and 24.6 weeks, respectively. Six-month progression-free survival was 19% for the entire group. Grade 3 or 4 toxicity developed in 14 patients (16%), one of whom developed pancreatitis and died. The results of this study demonstrate only modest efficacy for cRA therapy in this cohort of heavily pretreated patients with recurrent GBM. This data supports the use of cRA in such patients, but its further evaluation in larger, prospective, controlled studies with or without other noncytotoxic and cytotoxic agents may be warranted.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Confidence Intervals; Female; Glioblastoma; Humans; Isotretinoin; Karnofsky Performance Status; Male; Middle Aged; Neoplasm Recurrence, Local; Proportional Hazards Models; Retrospective Studies; Survival Analysis

Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Carboplatin; Carmustine; Dacarbazine; Disease Progression; Dose Fractionation, Radiation; Ependymoma; Gadolinium; Headache; Humans; Isotretinoin; Magnetic Resonance Imaging; Male; Neoplasm Recurrence, Local; Remission Induction; Tamoxifen; Temozolomide; Tomography, X-Ray Computed; Treatment Outcome

Hypercalcemia is a potential dosage-related adverse effect of 13-cis-retinoic acid in patients with neuroblastoma. Severe hypercalcemia requiring dosage reduction has been reported in children receiving 13-cis-retinoic acid 200 mg/m2/day and in those with concurrent renal impairment receiving 160 mg/m2/day. A 12-year-old girl without renal dysfunction, diagnosed with neuroblastoma, developed severe hypercalcemia requiring several hospitalizations while receiving 13-cis-retinoic acid 160 mg/m2/day. Her hypercalcemia resolved with hydration, diuretic therapy, and temporary discontinuation of 13-cis-retinoic acid. Despite a 50% dosage reduction to 80 mg/m2/day, severe hypercalcemia recurred with the next treatment cycle. Further treatment with 13-cis-retinoic acid was made tolerable by shortening the duration of the remaining cycles. Serum calcium levels should be monitored in patients with neuroblastoma who receive 13-cis-retinoic acid.

Topics: Brain Neoplasms; Child; Female; Humans; Hypercalcemia; Isotretinoin; Keratolytic Agents; Neoplasm Recurrence, Local; Neuroblastoma

Treatment of rat C6 glioma with high doses of 13 cis-retinoic acid (cRA) was responsible for death related to haemorrhagic necrosis localized to the tumor. Our aim was to explore this adverse effect of retinoid treatment. We show that cRA-treated C6 glioma at 25 mg/kg/day for 18 days exhibits in vivo an increase T-PA activity, which is responsible for a localized tumor fibrinolytic activity. Production of t-PA is supported by specific enhancement of gene expression, as was shown by the increase in t-PA mRNA (x 2.3). This production is a direct effect of cRA when treating the tumor, since tumor cells themselves do not produce enough t-PA and treatment of control rats does not increase the t-PA level. T-PA production by rat C6 glioma is in vivo related to the specific synthesis of t-PA by the C6 cell-line. The stimulation of C6 cell-line by cRA in vitro is dose-dependent and reached a maximum for 3 and 30 microM at the 72nd h. So cRA-treated C6 glioma cells produce t-PA which appears to be the major species associated with the fibrinolytic activity-induced intra-tumoral haemorrhage after exposure to retinoid treatment.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cerebral Hemorrhage; Death, Sudden; Drug Screening Assays, Antitumor; Female; Fibrinolysis; Gene Expression Regulation, Neoplastic; Glioma; Isotretinoin; Necrosis; Neoplasm Proteins; Neoplasm Transplantation; Rats; Rats, Sprague-Dawley; RNA, Messenger; RNA, Neoplasm; Tissue Plasminogen Activator; Tumor Cells, Cultured

Ganglioglioma is an uncommon brain tumor with glial and neuronal cellular components and a somewhat benign course. We are presenting an unusual case of ganglioglioma with malignant transformation in both cellular components associated with an aggressive clinical course. An almost complete resolution of the recurrent progressing tumor was achieved after treatment with cis-retinoic acid (cRA) as a single agent. A possible differential effect of cRA on the neuronal component of the tumor is suggested.

Topics: Adult; Antineoplastic Agents; Brain Neoplasms; Ganglioglioma; Humans; Isotretinoin; Magnetic Resonance Imaging; Male; Neoplasm Recurrence, Local

A patient with glioblastoma multiforme (GBM) who had failed conventional therapy was treated with IL-2 gene therapy. The patient received 10 subcutaneous immunizations with autologous tumor cells and fibroblasts genetically modified to secrete IL-2 by retroviral gene transfer. An antitumor immune response mediated in part by CD8+ cytotoxic T cells was demonstrated with the patient's peripheral blood mononuclear cells. A magnetic resonance imaging (MRI) scan performed 4 weeks after the highest treatment dose revealed marked tumor necrosis. These results support the evaluation of this form of IL-2 gene therapy in additional patients with glioblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cells, Cultured; Combined Modality Therapy; Fatal Outcome; Female; Fibroblasts; Genetic Therapy; Genetic Vectors; Glioblastoma; Humans; Injections, Subcutaneous; Interleukin-2; Isotretinoin; Lomustine; Magnetic Resonance Imaging; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Procarbazine; Radioimmunotherapy; Radiosurgery; Recombinant Fusion Proteins; Retroviridae; Salvage Therapy; T-Lymphocytes, Cytotoxic; Tamoxifen; Temporal Lobe; Transfection; Tumor Cells, Cultured; Vincristine

Successfully inducing differentiation in ectodermal diseases, retinoids harbour considerable therapeutic potential in the treatment of neuroectodermal-neuroepithelial malignancies. The principal tissue retinoid, retinoic acid, can be potently upregulated in vivo by a relatively specific catabolic inhibitor, R75251 (liarozole). Both substances have been given orally over 2 years in addition to standard treatment, and have been well tolerated. Corresponding closely to plasma retinoid levels, cutaneous side effects facilitate individual dosing. We evaluate this adjuvant retinoid approach and additional efforts to improve therapy of primary CNS malignancies, including the topical administration of retinoids in gamma linolenic acid.

Topics: Aged; Aged, 80 and over; Brain Neoplasms; Cell Differentiation; Central Nervous System Neoplasms; Combined Modality Therapy; Female; Glioblastoma; Humans; Imidazoles; Isotretinoin; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Retinoids; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Vitamin A