methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70025-7.pdf

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

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Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

The combinatorial synthesis of bicyclic privileged structures or privileged substructures

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

441 POSTER The G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors

NOUVEAUX DERIVES DE LA 3H-IMIDAZO 5,1-D TETRAZINE-1,2,3,5 ONE-4 DE FORMULE GENERALE (I) DANS LAQUELLE R EST HYDROGENE ALCOYLE, ALCENYLE OU ALCYNYLE (MAXIMUM 6C), NON SUBSTITUE OU SUBSTITUE PAR 1 A 3ATOMES D'HALOGENE OU RADICAUX CHOISIS PARMI ALCOXY ALCOYLTHIO, ALCOYLSULFINYLE, ALCOYSULFONYLE (MAXIMUM 4C) ET PHENYLE EVENTUELLEMENT SUBSTITUE, OU BIEN R EST CYCLOALCOYLE (3 A 8C) ET R EST CARBAMOYLE EVENTUELLEMENT SUBSTITUE PAR 1 OU 2 RADICAUX CHOISIS PARMI ALCOYLE ET ALCENYLE (MAXIMUM 4C) ET CYCLOALCOYLE (3 A 8C). CES NOUVEAUX DERIVES SONT UTILES COMME ANTI-CANCEREUX ET IMMUNOREGULATEURS. (CF DESSIN DANS BOPI)

Nouvelles imidazotetrazinones, leur preparation et les medicaments qui les contiennent

C8H7N7.HCl has a formula weight Mr237.7, and crystallizes in space group P21/n with a = 6.498(1), b = 10.333(8), c = 15.406(5) A, beta = 91.72(2) degrees. The final R factor was 0.049 for 1010 unique observed reflections. The azido substituent is almost linear, coplanar with the heterocycle, and parallel to the C(7)-C(6) ring bond. The heterocycle is protonated at N(1) and extensively hydrogen bonded. The 6-azido compound is at least a 100-fold better inhibitor of Escherichia coli dihydrofolate reductase than the analogue lacking the azido group, according to I50 values. Superimposing the quinazoline moiety upon the pteridine ring of the methotrexate-dihydrofolate reductase (E. coli) complex reveals two orientations of the N3 group in which it can fit the enzyme, making van der Waals contacts. Ab initio molecular orbital calculations suggest that one of these conformations, with torsion angle phi = C(5)-C(6)-N(61)-N(62) = -163.8 degrees, is low in energy.

Structural studies on bio-active compounds. Part 9. 2,4-Diamino-6-azidoquinazoline hydrochloride.

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Erratum: Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities (Journal of Experimental & Clinical Cancer Research (2014) 33 (81))

The in vitro cytotoxicity, stability, and metabolism of the 8-( N,N -dimethylcarboxamide) and 8-( N -methylcarboxamide) analogues of the experimental antitumor drug mitozolomide have been investigated in conjunction with their in vivo murine pharmacokinetics and metabolism.

When tested against the TLX5 lymphoma in vitro the ID50 values for dimethylmitozolomide, methylmitozolomide, and mitozolomide were 14.6, 3.0, and 2.3 µm, respectively. The cytotoxicity of dimethylmitozolomide was dramatically increased when it was incubated with murine hepatic microsomes. There was no significant difference in the in vitro stabilities of dimethylmitozolomide and methylmitozolomide with half-lives of 43.5 and 45.8 min, respectively, in RPMI at 37°C. The in vitro microsomal incubation of dimethylmitozolomide produced significant amounts of methylmitozolomide, which suggests that methylmitozolomide contributed to the cytotoxicity of dimethylmitozolomide in the presence of microsomes.

The pharmacokinetics of both dimethylmitozolomide and methylmitozolomide, given i.p. at 10 mg/kg, were investigated in CBA/Ca mice bearing the s.c. solid TLX5 lymphoma. Methylmitozolomide was absorbed rapidly with maximum plasma and tumor concentrations of 10.66 mg/liter and 8.01 mg/kg, respectively, achieved 0.17 h following dosing. Dimethylmitozolomide was also rapidly absorbed with maximum plasma and tumor concentrations of 9.34 mg/liter and 5.00 mg/kg, respectively, achieved within 0.18 h of dosing. Following administration of dimethylmitozolomide, methylmitozolomide was found in both plasma and tumor tissue. The plasma and tumor area under the curves of methylmitozolomide were 87.7% and 120.8%, respectively, of those seen when mice were dosed with authentic methylmitozolomide. By comparison of the area under the curves and clearance values, it was demonstrated that 89% of the administered dimethylmitozolomide was metabolized via methylmitozolomide.

Malcolm F. G. Stevens

Papers

441 POSTER The G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors

Nouvelles imidazotetrazinones, leur preparation et les medicaments qui les contiennent

Structural studies on bio-active compounds. Part 9. 2,4-Diamino-6-azidoquinazoline hydrochloride.

Erratum: Identification of novel RHPS4-derivative ligands with improved toxicological profiles and telomere-targeting activities (Journal of Experimental & Clinical Cancer Research (2014) 33 (81))

Metabolism and murine pharmacokinetics of the 8-(N,N-dimethylcarboxamide) analogue of the experimental antitumor drug mitozolomide (NSC353451).