Summary:To assess high-dose carboplatin chemotherapy with or without paclitaxel with filgrastim mobilized peripheral blood progenitor cell (PBPC) support in a phase I/II study, a total of 21 patients with mostly chemonaive disease received four cycles of high-dose chemotherapy. Cycle 1 (cyclophosphamide, 6 g/m 2 ) was followed by two cycles of carboplatin (1600 mg/m 2 or 1800 mg/m 2 ). Cycle 4 consisted of carboplatin (1600 mg/m 2 ), etoposide (1600 mg/m 2 ), and melphalan (140 mg/m 2 ). Further chemotherapy intensification was achieved by adding paclitaxel (175 mg/m 2 ) to all cycles with a fixed carboplatin dose (1600 mg/m 2 ). Ototoxicity was dose-limiting for escalation of sequential cycles of carboplatin. Grade 2 and grade 3 ototoxicity, hearing loss not requiring a hearing aid, or hearing loss correctable with a hearing aid, was observed with carboplatin at 1800 mg/m 2 . The maximum tolerated dose (MTD) of sequential carboplatin, therefore, was identified in this study as 1600 mg/m 2 . After cycles 1, 2, 3 and 4 the median duration of leukopenia (Ͻ1.0 ؋ 10 9 /l) was 7, 4, 4 and 6 days. Severe grade 3 and 4 infections were seen in only 7% of cycles. Of the 21 patients evaluable for disease response, 57% had complete remissions and 43% experienced partial remissions resulting in an overall response rate of 100%. The median progression-free survival is 25 (15-36) months, the median overall survial 36.5 (15-38) months. Most patients were suboptimally debulked or had bulky residual disease at the start of chemotherapy. Sequential high-dose chemotherapy to a maximum dose of 1600 mg/m 2 carboplatin is effective and feasible. A randomized, prospective trial comparing sequential high-dose chemotherapy with optimal standard chemotherapy is now warranted. Keywords: sequential high-dose chemotherapy; ovarian cancer; peripheral blood stem cell; autologous transplantation; maximum tolerated dose of carboplatin The prognosis for patients with advanced ovarian cancer remains poor in spite of the fact that combination chemotherapy, including platinum compounds, yields response rates between 60% and 80%. 1,2 Long-term disease control occurs in 20% to 30% of women with stage III disease, in less than 10% of women with incompletely resected stage III disease, and in less than 5% of women with stage IV disease. 3,4 These disappointing results are presumably due to the resistance of the disease to standard chemotherapy. 5 A retrospective analysis performed by Levin and Hryniuk 6 demonstrated a significant correlation between increased dose-intensity of cisplatin, response rate, and overall survival. Several randomized trials have addressed the role of dose intensity of chemotherapy in ovarian cancer. Maximum dose intensification in these studies was twofold. The results were inconclusive and the merit of dose intensification remains unproven. 7,8 According to in vitro studies, a minimum four-fold increase in dose intensity is necessary to overcome resistance to chemotherapy. 9-11 Single high-dose chemotherapy followed by stem c...

An efficient and practical process to generate beta-C-arylglucoside derivatives was achieved. The process described involves Lewis acid mediated ionic reduction of a peracetylated 1-C-aryl methyl glucoside derived from the addition of an aryl-Li to selectively protected delta-D-gluconolactone. The reduction of the 2-acetoxy-1-C-oxacarbenium ion intermediates proceeds with a high degree of selectivity to give beta-C-arylglucosides without 2-acetoxy group participation. Furthermore, during the reduction process we also identified an unprecedented critical role of water. By changing from the usual benzyl ether protecting groups because of cost and chemical compatibility concerns, the new process is made additionally efficient and highly selective.

An efficient synthesis of the monobactam aztreonam [[2S-[2r,3β(Z)]]-3[[(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-methyl-4-oxo-1-azetidinesulfonic acid] (1) by acylation of r-aminoazetidinone 22 with the regioselectively activated aminothiazoleiminoxyacetic diacid 15 or 18 is described. Reaction of benzhydryl ester 10 with N-hydroxybenzotriazole and dicyclohexylcarbodiimide followed by ester deprotection formed the monoacid amide 15. Alternatively, chemoselective transient silylation of the diacid 9 followed by activation with N-hydroxysuccinimide formed active ester 18. Acylation of r-aminoazetidinone 22 with amide 15 or ester 18 produced aztreonam (1) in 75-85% yield.

The synthesis of a number of new 1H‐pyrazolo[3,4‐b]pyridine‐5‐carboxylic acid derivatives is described. Most of these compounds have either an alkoxy or a basic substituent in position 4.

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