zd-9331 and Ovarian-Neoplasms

Thymidylate synthase (TS) has been targeted in cancer therapy for many years. As a result of a prolonged and extensive drug development program specific TS inhibitors have come into clinical practice. Following on from the development of the polyglutamatable TS inhibitor raltitrexed (Tomudex, ZD1694), ZD9331 is a rationally designed third-generation specific inhibitor of TS that does not require polyglutamation for its activity. Its development was based on the dual rationale of increased efficacy, by overcoming the potential for resistance due to reduced expression of folylpolyglutamate synthetase (FPGS), whilst potentially reducing the toxicities associated with polyglutamation and drug retention in normal tissues. Preclinical studies have shown it to be transported by the ubiquitously expressed reduced folate carrier as well as the alpha-folate receptor which is overexpressed in some cancers, especially ovarian. In vivo studies demonstrated a broad range of activity, leading to an extensive phase I program with several administration schedules. Whilst not being targeted to any individual tumor type, a large number of phase I, II, monotherapy and combination studies have been undertaken, and overall activity has been most promising, particularly in platinum-refractory relapsed ovarian, pancreatic and gastric cancers. Its role in the treatment of these diseases may be important, especially if patients were to be selected on the basis of their folate transport and FPGS status. The true potential of the drug remains to be determined.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Neoplasms; Ovarian Neoplasms; Quinazolines; Thymidylate Synthase

ZD9331 is an antifolate drug that potently and specifically inhibits thymidylate synthase (TS). In contrast with TS inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 (r=0.50; p=0.097) and raltitrexed (r=0.74; p=0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 (r=0.77; p=0.013) and raltitrexed IC50 (r=0.84; p=0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC50 ratios) (r=0.62; p=0.048). Similarly, cell lines with IC50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA (p=0.0087) compared with those with ratios

Topics: Antineoplastic Agents; Colonic Neoplasms; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Folic Acid Antagonists; Gene Expression; Humans; Ovarian Neoplasms; Peptide Synthases; Quinazolines; RNA, Messenger; RNA, Neoplasm; Thiophenes; Thymidylate Synthase; Tumor Cells, Cultured

Carboplatin is a better-tolerated alternative to cisplatin. JM216, the first p.o.-administrable platinum complex possesses toxicities comparable to carboplatin in Phase I studies. Together with the trans-platinum complex JM335, it provides new chemical guidelines for the development of compounds that may circumvent cisplatin resistance in tumors. Systematic structure-activity investigations have led to the discovery and development of ZD1694 (Tomudex), an inhibitor of thymidylate synthase that exploits both the reduced folate carrier and folylpolyglutamate synthetase as major determinants of its growth-inhibitory activity. Phase II studies have revealed encouraging activity against colon cancer, and Phase III studies are nearing completion. An associated structure-activity investigation has led to the development of ZD9331, a potent thymidylate synthase inhibitor which exploits the reduced folate carrier for cell entry, but which is independent of polyglutamation for its thymidylate synthase-inhibitory activity. This compound possesses antitumor activity in vivo and has been selected for full development.

Topics: Animals; Antineoplastic Agents; Cisplatin; Drug Resistance; Female; Humans; Leukemia L1210; Mice; Neoplasm Transplantation; Organoplatinum Compounds; Ovarian Neoplasms; Quinazolines; Structure-Activity Relationship; Thiophenes; Thymidylate Synthase

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

This Phase II, multicenter, open-label study was conducted to assess the efficacy and tolerability of ZD9331, a novel direct-acting thymidylate synthase inhibitor, in heavily pretreated patients with ovarian cancer.. The study recruited 44 women with ovarian cancer or primary peritoneal cancer previously treated with platinum therapy and paclitaxel and with progressive disease after, or intolerance to, topotecan administered as the most recent therapy. ZD9331 was administered as an intravenous infusion at 130 mg/m(2) on Days 1 and 8 of 3-week cycles, until objective evidence of disease progression. A cutoff date of 3 months after the last patient received the first dose was set for data collection.. Patients received a mean of 3.3 cycles of ZD9331 and a total of 143 cycles were administered. Among the 42 patients evaluated for best overall tumor response, one achieved a complete response and two achieved a partial response, giving an objective tumor response rate of 7%. The complete response occurred at Day 15 of Cycle 2 in a patient receiving ZD9331 as her eighth-line therapy. Seven patients had stable disease, giving a disease control rate of 23%. Thirty-one patients (71%) had disease progression and the median time to progression was 53 days. Most patients (89%) experienced drug-related adverse events, most commonly nausea (73%), vomiting (48%), and neutropenia (50%). Six patients (14%) were withdrawn from treatment due to adverse events.. The preliminary evidence of efficacy and acceptable tolerability of ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in a less heavily pretreated patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Infusions, Intravenous; Middle Aged; Ovarian Neoplasms; Quinazolines