A phase I study of combination chemotherapy with gemcitabine and oral UFT for advanced non-small cell lung cancer

A phase I study was carried out to determine the optimal dose and administration schedule for combined UFT plus gemcitabine therapy in patients with non-small cell lung cancer. Twenty-four patients (including 11 patients previously treated with cisplatin as the key drug) received oral UFT 400 mg m−2 on days 1 to 14 with intravenous infusions of gemcitabine (800 mg m−2 on days 8 and 15, or 900 mg m−2 on days 8 and 15, or 900 mg m−2 on days 1, 8 and 15). The most appropriate dosing option appeared to be 400 mg m−2 per day of oral UFT for 14 consecutive days with 900 mg m−2 gemcitabine on days 8 and 15. Eight of the 24 patients achieved partial response. The combination chemotherapy UFT and gemcitabine was well tolerated and may benefit patients with advanced non-small cell lung cancer. A multicentre phase II study using a 3-weekly regimen is in progress

Phase I trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

The objective of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of S-1, an oral fluorouracil derivative, combined with gemcitabine, the current standard treatment for advanced pancreatic cancer (APC). The subjects were histopathologically proven APC patients with distant metastasis. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this was repeated every 21 days. Doses of each drug were planned as follows: level 1: 800/60, level 2a: 800/80, level 2b: 1000/60, level 3: 1000/80 (gemcitabine (mg m−2)/S-1 (mg m−2 day−1)). In all, 21 patients with APC were enrolled. The main grade 3–4 toxicities observed during first cycle were neutropenia (33%), anaemia (10%), thrombocytopenia (14%) and anorexia (10%). There were no DLT observed in level 1. Three of six patients in level 2a had DLT and this level was considered the MTD. In all, 12 patients in level 2b had no DLT and this level was selected as the recommended dose. Applicable responses were one complete response and nine partial responses (48%). As toxicities were well tolerated and antitumour activities seem to be promising, this combination can be recommended for further phase II studies with APC

New insights into the synergism of nucleoside analogs with radiotherapy

Nucleoside analogs have been frequently used in combination with radiotherapy in the clinical setting, as it has long been understood that inhibition of DNA repair pathways is an important means by which many nucleoside analogs synergize. Recent advances in our understanding of the structure and function of deoxycytidine kinase (dCK), a critical enzyme required for the anti-tumor activity for many nucleoside analogs, have clarified the mechanistic role this kinase plays in chemo- and radio-sensitization. A heretofore unrecognized role of dCK in the DNA damage response and cell cycle machinery has helped explain the synergistic effect of these agents with radiotherapy. Since most currently employed nucleoside analogs are primarily activated by dCK, these findings lend fresh impetus to efforts focused on profiling and modulating dCK expression and activity in tumors. In this review we will briefly review the pharmacology and biochemistry of the major nucleoside analogs in clinical use that are activated by dCK. This will be followed by discussions of recent advances in our understanding of dCK activation via post-translational modifications in response to radiation and current strategies aimed at enhancing this activity in cancer cells

Raltitrexed plus gemcitabine (TOMGEM) in advanced pancreatic cancer. Results of a Belgian multicentre phase II study.

This multicenter phase II study was designed to determine the activity and tolerance of gemcitabine and raltitrexed in advanced pancreatic adenocarcinoma.Clinical TrialClinical Trial, Phase IIJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe