zd-9331 and Breast-Neoplasms

Non-small cell lung cancer (NSCLC), ovarian and breast cancers, especially in advanced stages, are difficult to treat using chemotherapy, and novel treatments are required to improve the outcome for the large numbers of patients who relapse after receiving the most effective first- and second-line treatments currently available. This paper reviews the results from three trials of ZD9331, a novel, direct-acting antifolate, in patients with relapsed or refractory solid tumours.. Patients with relapsed or refractory NSCLC, ovarian or breast cancer were included in these three open-label, multicentre trials. All three trials included an i.v. arm of ZD9331 at a dose of 130 mg/m2; the ovarian study also included a 65 mg/m2 i.v. treatment arm and the breast cancer trial included a 3 mg oral treatment arm. Patients received ZD9331 as a 30-min i.v. infusion once weekly for 2 weeks followed by 1 week without treatment (3-week cycle). Oral ZD9331 was given once daily for 28 consecutive days and repeated every 6 weeks.. One hundred and eighty-nine patients were included in the three trials (NSCLC: n = 46; ovarian: n = 80; breast: n = 63). Neutropenia (45-59%), asthenia (25-42%) and nausea (41-59%) were amongst the most common adverse events observed in all three trials; however, in the oral treatment group of the breast cancer trial anaemia (58%) and increased alanine aminotransferase (45%) or aspartate aminotransferase (39%) were also frequent. There were no objective responses seen in the NSCLC trial; 20 of 46 patients (43.5%) experienced a best overall response of stable disease. Objective response rates (ORRs) in the ovarian trial were 2.5% (one patient) and 10% (four patients) in the 65 and 130 mg/m2 treatment arms, respectively. In the breast cancer trial ORRs were 9.7% (three patients) and 12.5% (four patients) in the oral and i.v. groups, respectively.. ZD9331 has a manageable toxicity profile, and shows some evidence of activity in patients with relapsed or refractory NSCLC, ovarian and breast cancer.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Quinazolines

The folate analogue BGC9331 is a new thymidylate synthase (TS) inhibitor showing a broad spectrum of cyto-toxic activity against several human solid tumors, including colorectal cancer. In this study, we investigated the anticancer activity of BGC9331 either alone or combined with 5-fluorouracil (5-FU), MTA (multi-target antifolate), oxali-platin and SN-38, the active metabolite of the topoisomerase I inhibitor CPT-11. The antiproliferative activity of each drug and BGC9331-based combinations was investigated in the HT-29 human colorectal cancer cell line and its HT-29/5-FU counterparts selected for resistance to 5-FU. BGC9331 combined with MTA or SN-38 induced synergistic responses in HT-29 cells. Treatment of HT-29 cells with either BGC9331 or SN-38 increased caspase-3 activity and the percentage of apoptotic cells from 3 to 13%. Both drugs also augmented the proteolytic cleavage of the Rho-kinase ROCK-1 that was attenuated by the caspase-3 pathway inhibitor z-DEVD-fmk. BGC9331 combined with SN-38 further increased the percentage of apoptotic cells to 25%, and inhibited cell cycle progression and cell proliferation by 65%. This was accompanied by proteolytic activation of ROCK-1, through both caspase-3-dependent and -independent mechanisms, as shown in caspase-3-deficient MCF-7 breast cancer cells. These encouraging results warrant further preclinical investigations and clinical trials on the use of BGC9331 combined with SN-38/CPT-11 in treatment of patients with advanced colorectal or gastric cancers.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Camptothecin; Caspase 3; Caspase Inhibitors; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Cysteine Proteinase Inhibitors; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Fluorouracil; Folic Acid Antagonists; Glutamates; Guanine; HT29 Cells; Humans; Intracellular Signaling Peptides and Proteins; Irinotecan; Oligopeptides; Organoplatinum Compounds; Oxaliplatin; Pemetrexed; Protein Serine-Threonine Kinases; Quinazolines; rho-Associated Kinases; Thymidylate Synthase; Time Factors; Topoisomerase I Inhibitors