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PubMed2006

Primary and metastatic brain tumors.

High-grade malignant gliomas (HGG) are the most common and malignant primary central nervous system tumors. Despite therapeutic efforts and advances in biologic knowledge, these diseases remain lethal. Standard treatment of HGG is based on surgery and radiotherapy, usually followed by adjuvant chemotherapy. Many randomized trials addressing the role of post-radiation or "adjuvant" chemotherapy have been conducted in the last three decades, yielding inconclusive results. However, a statistically significant survival benefit with adjuvant chemotherapy has been demonstrated in two meta-analyses with nitrosourea-based adjuvant chemotherapy and a recent phase III trial has demonstrated a survival advantage for radiotherapy with concomitant and adjuvant temozolomide (TMZ) in patients with newly diagnosed glioblastoma. Since high-grade malignant gliomas can seldom be cured, the primary aim of treatments for recurrent disease is to improve progression-free survival (PFS), and to improve or preserve neurological functions. TMZ showed activity even in the treatment of recurrent HGG with a good toxicity profile, whether few data are available for effective treatments in patients treated with adjuvant TMZ. As a result, new agents and novel approaches are required. Furthermore, molecular studies to evaluate chemosensitivity predictors are necessary for patients' selection. Brain metastases are estimated to occur in 20% to 40% of cancer patients, with a higher risk in lung cancer, breast cancer and melanoma. The incidence of brain metastases is rising as results of better imaging procedures and improvements in treatments which leave more cancer patients at risk as survival increases. The prognosis is dependent on a number of factors such as histology of primary tumor, performance status, localization number and size of brain metastases and status of extra cranial disease. Surgery and radiotherapy are indicated in controlled disease with isolated brain metastases. Systemic chemotherapy represents he optimal treatment in chemosensitive tumors with multiple or isolated brain metastases.

Journal Article↗
PubMedDate not supplied

Post-operative combined radiation and chemotherapy with temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker evaluation.

BACKGROUND: Clinical studies have shown that temozolomide (TMZ) and irinotecan demonstrate activity in high grade astrocytic tumors (HGAT). However, the optimal schedule of administration is unknown. PATIENTS AND METHODS: In the present study, a total of 45 HGAT patients, 38 with glioblastoma multiforme (GBM) and 7 with anaplastic astrocytoma (AA), were treated with TMZ, 150 mg/m(2) on days 1-5, followed by irinotecan, 150 mg/m(2) on days 6 and 17, every 4 weeks for 6 cycles or until the occurrence of unacceptable toxicity or disease progression. Radiation therapy (60 Gy) was initiated on the first day of treatment. RESULTS: Twenty-two patients completed six cycles of treatment. Most frequently recorded side-effects included neutropenia (37%), nausea/vomiting (66%), diarrhea (31%) and infection (44%). Five episodes of vaso-occlusive disease, all of them fatal, were observed. After a median follow-up of 49.8 months, median progression-free survival for patients with GBM was 7.7 months, while median overall survival was 12.8 months. There were six long-term survivors, three of them with GBM. Two out of the five biomarkers studied, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor-C (VEGF-C), were found to be overexpressed in 74% of the tumors, however they had no predictive value for progression-free or overall survival. CONCLUSION: The combination of TMZ and irinotecan, as administered in this study, was accompanied by high rates of toxicity, especially myelotoxicity and infection. Further development of this regimen in the treatment of HGAT is not recommended.

Adult↗
PubMedDate not supplied

Metabolism of diazepam in vitro by human liver. Independent variability of N-demethylation and C3-hydroxylation.

The interindividual variability of diazepam metabolism was studied using human livers. The formation of N-desmethyldiazepam (NDZ) and 3-hydroxydiazepam (temazepam, TMZ), was monitored by gas chromatography. In 10 livers, Km values for NDZ and TMZ formation varied independently from each other, each by a factor of 4, from 100 to 400 microM. This variability is consistent with the presence of at least two different cytochrome P-450 species controlling formation of these metabolites. In the same livers, Vmax for NDZ and TMZ production varied 6-fold and 15-fold, respectively.

Anti-Anxiety Agents↗
PubMed1996

Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea.

Cells with the mutator phenotype are tolerant to methylating damage from N-methylnitrosourea and N-methyl-N'-nitro-N-nitrosoguanine, exhibit replication repair errors, and have recently been found to be mutant in mismatch repair (MMR). However, resistance of cell lines with these defects to clinically used chemotherapeutic agents and the relationship of this resistance to expression of O6-alkylguanine-DNA alkyltransferase (AGT), which repairs DNA damage caused by methylating agents, has not been demonstrated. We compared resistance to the methylating agent temozolomide (TMZ) and to the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with and without AGT inhibition by 06-bG in several colorectal carcinoma cell lines. Two cell lines had known microsatellite instability (replication repair error-positive) and high levels of AGT, as well as a mutation in one of two MMR genes, hMLH1 (HCT116) or GTBP (HCT15). Cell line SW480 had wild-type MMR genes and high AGT, and HCT116+Ch3 has previously been transduced with chromosome 3 (carrying wild-type hMLH1) and thus has a "corrected" MMR phenotype. SW480 exhibited the expected sensitivity to TMZ and BCNU and marked potentiation of cytotoxicity by O6-bG. In contrast, HCT15 and HCT116 were markedly resistant to TMZ and were not sensitized by O6-bG-mediated inhibition of AGT, whereas the sensitivity pattern in HCT116+Ch3 cells was similar to that in SW480. All cell lines were sensitized to BCNU by O6-bG. Thus, tumor cells with defects in MMR appear particularly resistant to methylating agents in a manner that overrides dependence on AGT and its inhibition by O6-bG. However, these cells use AGT for resistance to chloroethylating agents, providing an alternative strategy for alkylating agent therapy.

Antineoplastic Agents, Alkylating↗
PubMed1999

Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism.

Eight inhibitory monoclonal antibodies (MAbs) individually specific to human cytochrome P-450 (P-450) 1A1, 1A2, 2A6, 2B6, 2C subfamily (2C8, 2C9, 2C18 and 2C19), 2D6, 2E1, and 3A4/5 were used to define the role of single P-450s in the metabolism of diazepam (DZ), 7-ethoxycoumarin (7-EC), and imipramine (IMI) in human liver microsomes (HLM). The MAbs were added combinatorially to six HLM samples. With DZ as a substrate, more than 80% of temazepam (TMZ) formation was inhibited in all six samples by the addition of MAb to 3A4/5, indicating an 80% contribution of 3A4/5 to TMZ formation. Nordiazepam formation was inhibited with MAbs to 2B6 (6-23%), 2C subfamily (12-61%) and 3A4/5 (14-45%). The MAbs to 1A1, 1A2, 2A6, 2D6, and 2E1 did not inhibit TMZ or nordiazepam formation; this indicates their noninvolvement in DZ metabolism. The MAb-defined P-450 contribution to 7-EC Odeethylation in six HLM samples was 17 to 60% for 2E1, 15 to 46% for 2A6, and 5 to 22% for 1A2, reflecting the role and variation of each P-450 in this activity. MAbs to 1A1, the 2C subfamily, 2D6, and 3A4/5 did not affect 7-EC metabolism in the HLM samples. IMI is metabolized mainly to 2-hydroxyimipramine by expressed 2C19 and 2D6, and desipramine (DIM) by expressed 1A2, 2C18, 2C19 and 2D6. Expressed 1A1, 2C9, and 3A4 showed low activities for the formation of DIM. Of six HLM samples, five showed IMI hydroxylation activity (0.35-2.6 nmol/min/nmol P-450) while one (HL43) lacked hydroxylation activity. All six HLM samples showed N-deethylation activity (0.74-1.4 nmol/min/nmol P-450). The MAb-determined contribution of 2D6 and 2C19 to 2-hydroxyimipramine formation ranged from 47 to 90% and from 0 to 49%, respectively, while HL43 did not show 2-hydroxylation. The role of P-450s involved in DIM formation varied for 2C19 (13-50%), 1A2 (23-41%), and 3A4 (8-26%). These studies demonstrate a system for identifying the quantitative metabolic role of single P-450s and their interindividual variability in a tissue containing multiple P-450s. The system using inhibitory MAbs is simple, precise, and applicable to any P-450-mediated catalytic activity including that for drugs, carcinogens, mutagens, toxic chemicals and endobiotics.

Antibodies, Monoclonal↗
PubMed2006

Salvage chemotherapy with cyclophosphamide for recurrent temozolomide-refractory anaplastic astrocytoma.

BACKGROUND: A prospective Phase II study of cyclophosphamide (CYC) was conducted in adult patients with recurrent temozolomide-refractory anaplastic astrocytoma (AA) with a primary objective of evaluating 6-month progression-free survival (PFS). METHODS: Forty patients (28 men, 12 women) ages 26-57 years (median, 43 yrs) with neuroradiographically recurrent AA were treated. All patients had previously been treated with surgery and involved-field radiotherapy. Additionally, all patients were treated with temozolomide (TMZ) chemotherapy after radiotherapy. All patients were treated at recurrence with CYC administered intravenously on 2 consecutive days (750 mg/m2/day) every 4 weeks (operationally defined as a single cycle). Neurologic and neuroradiographic evaluation were performed every 8 weeks. RESULTS: All patients were evaluable. A total of 215 cycles of CYC (median, 4 cycles; range 2-12 cycles) was administered. CYC-related toxicity included alopecia (all patients, 100%), anemia (5, 12.5%), thrombocytopenia (6, 15%), and neutropenia (8, 20%). Four (10%) patients required transfusion. Nine patients (22.5%) (95% confidence interval [95% CI], 11%-39%) demonstrated a neuroradiographic partial response, 16 patients (40.0%) (95% CI, 25%-57%) demonstrated stable disease, and 15 patients (37.5%) (95% CI, 23%-54%) had progressive disease after 2 cycles of CYC. Time to tumor progression ranged from 2-19 months (median, 4 mos; 95% CI, 2-6 mos). Survival ranged from 2-26 months (median, 8 mos; 95% CI, 6-10 mos). The 6-month and 12-month PFS was 30% and 8%, respectively. CONCLUSIONS: CYC demonstrated modest efficacy with acceptable toxicity in this cohort of adult patients with recurrent anaplastic astrocytoma, all of whom had failed prior TMZ chemotherapy.

Adult↗
PubMed2006

Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma.

BACKGROUND: Patients with metastatic melanoma (MM) have very few therapy options. Based on reports of responses to paclitaxel and carboplatin (PC), 31 patients with MM were treated with PC. METHODS: Data regarding patients treated with PC were abstracted from medical records. Clinical outcomes as determined by the treating oncologist were used for this analysis. Response determination was retrospectively confirmed using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-one patients with MM were treated with PC. Patients had a median of 2 previous therapies, with the majority (29; 94%) having failed prior temozolomide (TMZ) or dacarbazine (DTIC) therapy. The most commonly used regimen was weekly paclitaxel (at a dose of 100 mg/m(2)) and carboplatin (area under the curve 2) administered on Days 1, 8, and 15 of a 28-day cycle. An objective partial response was noted in 8 patients (26%) with an additional 6 patients (19%) having stable disease; therefore, a clinical benefit was noted in 45% of those patients treated. The median time to disease progression for the entire group was 3 months (range, 0-7 mos), with a median overall survival of 7.8 months (range, 1-14 mos). The clinical benefit derived by the 14 patients, which lasted for a median of 5.7 months (range, 2.5-7.3 mos), was considered to be clinically significant. At the time of last follow-up, eight patients continued to receive PC therapy. CONCLUSIONS: The PC combination appears to have definite and clinically meaningful activity when used as second-line therapy after TMZ or DTIC. Further evaluation of this regimen, alone or as a 'backbone' for other agents, needs to be considered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Pharmaceutical-mediated inactivation of p53 sensitizes U87MG glioma cells to BCNU and temozolomide.

Pifithrin-alpha (PFTalpha) is a small molecule inhibitor of p53. By reversibly blocking apoptosis in response to DNA damage, PFTalpha protects normal cells from lethal doses of gamma-radiation (Komarov et al., Science, 1999;285:1733-7). We examined the effect of PFTalpha on the chemosensitivity of a human cancer in which cell cycle arrest, not apoptosis, is the principle cellular consequence of p53 activation. This was of interest because E6 silencing of p53 sensitizes U87MG astrocytic glioma cells to BCNU and temozolomide (TMZ), cytotoxic drugs that are modestly helpful in the treatment of aggressive astrocytic gliomas. We observed that exposure of U87MG cells to PFTalpha before cytotoxic chemotherapy attenuated p53-mediated induction of p21WAF1 protein levels, sensitizing U87MG cells to BCNU and TMZ. Sensitization of U87MG cells was associated with G1 arrest, delayed entry into S-phase and decreased repair of DNA damage by BCNU. Our findings suggest that in addition to protecting normal cells from the toxic effects of radiation and chemotherapy, small molecule inhibitors of p53, like PFTalpha, might play a role in clinical oncology by sensitizing certain resistant cancers to cytotoxic chemotherapies.

Antineoplastic Agents, Alkylating↗
PubMed2006

Temozolomide in resistant or relapsed pediatric solid tumors.

PURPOSE: We report the off-label study aimed at investigating the use of temozolomide (TMZ) as single agent in relapsed or resistant pediatric solid tumors. The drug was administered at the dose of 215 mg/m2/day x 5 days or 180 mg/m2/day x 5 days in patients with prior craniospinal irradiation (CSI) or autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Fifty two patients, median age 127.6 months, with resistant or relapsed solid tumors were enrolled. Tumor types were: neuroblastoma (NB; n = 17), medulloblastoma (MB; 8), brain stem glioma (BSG; 8), extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor (EOES; 4), Ewing's sarcoma (ES; 4), anaplastic astrocytoma (AA; 3), rhabdomyosarcoma (RMS; 2), ependymoma (EP; 2), cerebral primitive neuroectodermal tumor (cPNET; 2), hepatocarcinoma (HC; 1), and osteosarcoma (OS; 1). All patients were pre-treated. Two outpatient courses were administered, with a median of 4.8 courses/pt. RESULTS: Objective response-rate (CR + PR + MR) in our series was 13.4% (1.9% CR, 3.8% PR, and 7.7% MR), SD occurred in 38.4% of patients and 48% had PD. The median survival was 7.8 months (range 1-37) and median time to progression was 3.4 months (range 1-20); these data were significantly correlated with histology and previous nitrosureas administration in multivariate analysis. Haematological toxicity grade 3-4 (mainly thrombocytopenia) was observed in 21.4% of administered courses, nausea was reported in 3.1% and respiratory distress in 0.7%. CONCLUSION: Oral TMZ was well tolerated in children with resistant or relapsed solid tumors and showed activity in NB and CNS tumours refractory to standard chemotherapy.

Adolescent↗
PubMed2001

Protection and in vivo selection of hematopoietic stem cells using temozolomide, O6-benzylguanine, and an alkyltransferase-expressing retroviral vector.

Transfer of drug resistance genes to hematopoietic stem cells offers the potential to protect cancer patients from drug-induced myelosuppression and to increase the number of gene-modified cells by in vivo selection. In this study, a retroviral vector expressing both a P140K variant of human O6-methylguanine-DNA methyltransferase (MGMT) and an EGFP reporter gene was evaluated for stem cell protection in a murine transplant model. Mice transplanted with vector-transduced cells showed significant resistance to the myelosuppressive effects of temozolomide (TMZ), an orally administered DNA-methylating drug, and O6-benzylguanine (BG), a drug that depletes cells of wild-type MGMT activity. Following drug treatment, increases in EGFP(+) peripheral blood cells were seen in all peripheral blood lineages, and secondary transplant experiments proved that selection had occurred at the stem cell level. In a second set of experiments in which transduced cells were diluted with unmarked cells, efficient stem cell selection was noted together with progressive marrow protection with repeated treatment courses. Altogether, these results show that P140K MGMT gene transfer can protect stem cells against the toxic effects of TMZ and BG and that this vector/drug system may be useful for clinical myeloprotection and for in vivo selection of transduced stem cells.

Alkyl and Aryl Transferases↗
PubMed1993

Intracoronary trimetazidine does not improve recovery of regional function in a porcine model of repeated ischemia.

We evaluated the effect of trimetazidine (TMZ) on recovery of regional cardiac function in anesthetized open-chest pigs, subjected to fifteen 2-minute occlusions of the left anterior descending coronary artery, separated by 2 minutes of reperfusion and a 120-minute recovery period. Regional myocardial function was evaluated by sonomicrometry-derived segment lengthening and the area enclosed by the left ventricular pressure-segment length loop (external work, EW) in animals, which received either an intracoronary infusion of TMZ (33 micrograms/kg/min, n = 6) or saline (1 ml/min, n = 7), starting 15 minutes before the first occlusion and ending 2 minutes after the 15th occlusion. In addition, myocardial malondialdehyde production to evaluate oxygen free radical production, oxygen consumption, and the ATP, ADP, and AMP content, as well as the energy charge, were determined at regular time intervals. In control pigs the sequences of occlusion-reperfusion did not affect systemic hemodynamics, except for the LVdP/dtmax, which decreased by 11% during the interventions and did not recover during the following reperfusion period of 2 hours (78% of baseline, p < 0.05). Systolic segment length shortening and EW were increased at the end of the first occlusion-reperfusion cycle, decreased gradually during the remainder of the occlusion-reperfusion periods, and did not improve during the recovery period. Energy charge and myocardial blood flow were not impaired, but oxygen consumption was decreased during the recovery period. The malondialdehyde data did not provide evidence for production of oxygen free radicals.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed2004

The acute effect of trimetazidine on the high frequency fatigue in the isolated rat diaphragm muscle.

The objective of this study was to determine the acute effect of trimetazidine (TMZ) on the pre-fatigue, fatigue and post-fatigue contractile characteristics and tension-frequency relationships of isolated rat diaphragm muscle. Muscle strips were taken from the ventral-costal aspects of the diaphragm muscle of rats killed by decapitation. The muscle strips were suspended in organ baths containing Krebs solution, with a gas mixture of 95% O2 and 5% CO2 at 37 degrees C and pH 7.35-7.45. After determining the thermoregulation and optimum muscle length the muscles were subjected to direct supramaximal stimulation with 0.05 Hz frequency square pulses for periods of 0.5 msec to obtain control values. After adding 5 x 10(-6) and 5 x 10(-5) M trimetazidine solution to the respective bath media, the contractile parameters of the muscles were recorded. The contractile parameters were also recorded for both the trimetazidine and trimetazidine-free media after application of the high frequency fatigue protocols. Later, the tension-frequency relationship was determined by applying stimulating pulses of 10, 20, 50 and 100 Hz to the muscle strips. Whilst the twitch tension obtained from the 5 x 10(-6) and 5 x 10(-5) M trimetazidine media showed numerical increases compared to that of the controls, these were not statistically significant (p>0.05). The contraction time exhibited a dose dependent increase (p<0.001), whilst the contraction and relaxation rates did not differ significantly. The isometric contraction forces obtained with the different stimulating frequencies showed a significant increase in the tetanic contraction only at 100 Hz (p<0.05). A comparison of the pre- and post-fatigue twitch tensions in the trimetazidine media showed the post- fatigue twitch tensions to be significantly higher than those of the pre-fatigue contraction forces (p<0.05). In the 5 x 10(-6) and 5 x 10(-5) M trimetazidine media the increases in the post-fatigue contraction force were 22 and 30%, respectively. These results demonstrated that in isolated rat diaphragm muscle, TMZ significantly limited the mechanical performance decrease during fatigue. It is our opinion that trimetazidine contributed to the observed fatigue tolerance by eliminating the factors of fatigue, due to preservation of intracellular calcium homeostasis, provision of the ATP energy levels needed by ATPase dependent pumps and especially by keeping the intracellular pH within certain limits.

Animals↗
PubMed2005

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours.

OBJECTIVE: A combination regimen of temozolomide (TMZ) and pegylated liposomal doxorubicin has been evaluated in the treatment of brain metastases from solid tumours. STUDY DESIGN: Nineteen consecutive patients (pts) have been enrolled in a prospective phase II trial and treated with TMZ 200 mg/m2 (days 1-5) and pegylated liposomal doxorubicin 35 mg/m2 (day 1) every 28 days. The study was prospectively projected according to the Simon's two-stage optimal design. RESULTS: Major toxicities have been grade III neutropenia and thrombocytopenia in one patient (pt) and grade III erythrodisesthesia in two pts. Three pts achieved a complete response (CR) and four a partial response (PR), for an overall response rate of 36.8% (95% CI: 19.1-59.2), which exceeded the target activity in the study design. A significant improvement in quality of life was demonstrated by FACT-G analysis. The median Progression Free Survival (PFS) was 5.5 (95% CI: 2.7-8.2) months while the median Overall Survival (OS) was 10.0 months (95% CI: 6.3-13.7). CONCLUSIONS: The TMZ/pegylated liposomal doxorubicin regimen was well tolerated with an encouraging activity in brain metastases from solid tumours.

Administration, Oral↗
PubMed2005

Expression of ABC-1 transporter is elevated in human glioma cells under irradiation and temozolomide treatment.

OBJECTIVE: Chemo-therapeutic treatment of glioma patients has minor success. Little is known about mechanisms of a pronounced resistance of gliomas towards actual therapies, yet. ABC-1 belongs to the group of transporters known to be involved in the export of hydrophobic substances and vascular regulation. This study investigates an effect of both temozolomide (TMZ) treatment and/or irradiation on the expression of the ABC-1 transporter in human U87-MG glioma cells. MATERIAL AND METHODS: In parallel experiments U87-MG cells underwent either irradiation (RT), chemo-treatment (CT) using TMZ, and combined chemo/radiation-treatment (CT/RT). After each treatment the cells were incubated either 2 or 24 hours at 37 degrees C and counted before protein analysis using Western-Blot technique. RESULTS AND CONCLUSIONS: An exponential growth of cellular density was observed for both untreated and irradiated cells being, however, about 2-times slower in irradiated compared to untreated cells. In contrast the density increase of chemo-treated cells as well as that of cells, which underwent the combined CT/RT treatment was of linear nature. ABC-1 expression was detected in untreated as well as treated cells. Increasing cell density and all kinds of treatment resulted in a considerably enhanced ABC-1 expression. CT treatment resulted in highly up-regulated ABC-1 expression especially in non-confluent cultures compared to untreated cells. Irradiation had a comparable or even higher inducible effect on the ABC-1 expression rates depending, however, on cell density. The highest expression rates were observed in cultures with high cellular density 2 hours after application of the combined treatment. Strong up-regulation of ABC-1 expression under both irradiation and chemo-treatment might be a clue to multidrug and irradiation cross-resistance mechanisms of malignant glioma cells converting the ABC-1 transporter into an attractive pharmacological target for a clinical breakthrough in the therapy of malignant gliomas.

ATP-Binding Cassette Transporters↗
PubMed2006

Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma.

Concurrent temozolomide (TMZ) and radiotherapy is the new standard of care for patients with newly diagnosed glioblastoma. In 51 consecutive patients treated according to this regimen, 7 patients (14%) manifested surgically confirmed early necrosis without evidence of recurrent tumor. This observation suggests that daily TMZ may represent a potent radiosensitizing regimen.

Adult↗
PubMed2006

A pilot study of primary temozolomide chemotherapy and deferred radiotherapy in elderly patients with glioblastoma.

There is no standard of care for elderly patients (age>or=70 years) with newly diagnosed glioblastoma (GBM). In 15 consecutive patients (median age 79 years) treated with temozolomide (TMZ) (42 days on; 14 days off), median survival was 6 months (range 4-14 months). This pilot study suggests that low dose daily TMZ may represent an alternative and equally effective treatment to more traditionally administered radiotherapy.

Aged↗
PubMed2005

Adjuvant chemotherapy in the treatment of high grade gliomas.

Standard treatment of high-grade glioma (HGG) is based on surgery followed by limited field radiotherapy, while the role of chemotherapy is still controversial. Many randomized trials addressing the role of post-radiation or "adjuvant" chemotherapy have been conducted in the last three decades, yielding negative or inconclusive results. A statistically significant survival benefit with adjuvant chemotherapy has been demonstrated in two meta-analyses. The estimated absolute increase in survival is modest (10% at 1 year) but significant, and it appears independent of age, Performance Status and histology. Nitrosourea-based regimens were long considered the standard chemotherapy options for HGG, but their toxicity is not negligible. Temozolomide (TMZ) is a promising new drug that seems to be effective in patients with recurrent disease. Clinically and statistically significant survival benefit with the administration of TMZ concomitant and after radiotherapy has been recently demonstrated, establishing a new standard in HGG adjuvant treatment. Randomized comparisons with nitrosoureas are lacking and represent a major issue to be studied in future phase III trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.

Animals↗