Yoshiko Akiyama

In vitro effects of combinations of cis-amminedichloro (2-methylpyridine) platinum (II) (ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line

Among numerous clinical regimens of combination chemotherapy, synergy has been observed to be particularly marked with combinations containing cisplatin (CDDP). However, the clinical use of CDDP has sometimes been limited by acquired resistance. The new-generation platinum drug, ZD0473, was synthesized with the aim of hindering the reaction of the drug with thiols, by the introduction of a 2-methylpyridine ligand. This enables the drug to exert antitumor activity against cisplatin-resistant cancer cells with elevated glutathione and/or metallothionein levels. The drug was also shown experimentally to overcome cisplatin resistance due to impaired drug accumulation, and enhanced DNA repair/tolerance to platinum-DNA adducts. We investigated the effects of combinations of ZD0473 with other anticancer drugs on the growth of a human small-cell lung cancer cell line (SBC-3). Six novel anticancer drugs were tested: docetaxel (TXT), paclitaxel (TXL), vinorelbine (VNB), irinotecan (CPT-11), gemcitabine (GEM) and pemetrexed (MTA). The growth inhibitory effect of the drugs was measured by MTT assay and the effects of the combination regimens were evaluated by the combination index analysis method developed by Chou and Talalay. Synergy was demonstrated for the combination regimens of ZD0473-GEM and ZD0473-TXL, while an additive effect was observed with combinations containing TXT, VNB, CPT-11 or MTA. In the case of the ZD0473-GEM combination, synergy was observed over a wide range of inhibition levels at dose ratios of 50:1, 100:1 and 250:1. The level of synergy was equivalent to that observed for combinations of CDDP-etoposide, CDDP-GEM and nedaplatin-CPT-11. The results suggest that the combination of ZD0473 with GEM merits further investigation in small cell lung cancer.

A phase I/II trial of cisplatin, docetaxel and ifosfamide in advanced or recurrent non-small cell lung cancer.

This trial was initiated to evaluate the toxicity and activity of combination chemotherapy employing cisplatin (CDDP), docetaxel (DCT) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), and to determine the maximum tolerated dose (MTD) of IFX. Chemotherapy-naive patients with advanced or recurrent NSCLC received 60 mg/m(2) DCT followed after a 3-h interval by 60 mg/m(2) CDDP on chemotherapy day 1, and IFX at an escalating dose with mesna protection on days 2-4. The chemotherapy was repeated every 3 weeks. Granulocyte colony-stimulating factor (GCSF) was administered in the event of grade 3 leukopenia/neutropenia. The patients tolerated the treatment well up to level 4 of IFX dosing 1.5 g/day, but not the IFX dose at level 6 (2.0 g/day). Additional patients were enrolled in level 5 (IFX 1.7 g/day) to evaluate the toxicity of the drugs around the MTD. Level 5 was also judged as having exceeded the MTD, with febrile neutropenia and hepatic toxicity being observed as the dose-limiting toxicities. No toxicity-related deaths occurred. The majority of the chemotherapy courses were supported by GCSF administration. A total of 33 eligible patients were entered into the trial; the overall response rate was 10/33 or 30% among all eligible cases, and the rate for patients treated with the MTD or higher (levels 4-6) was 8/24, or 33% (90% confidence limit: 18-52%). The MTD of IFX was 1.5 g/m(2) administered for 3 days in this triplet combination. The clinical activity does not seem to justify the toxicity profile.

CPT-11 Alters the Circadian Rhythm of Dihydropyrimidine Dehydrogenase mRNA in Mouse Liver

Combination chemotherapy consisting of 5‐fluorouracil (5‐FU) and 7‐ethyl‐10‐[4‐(l‐piperidino)‐l‐piperidino]carboxycamptothecin (CPT‐11) is a promising regimen for gastrointestinal cancer. The circadian‐dependent efficacy and toxicity of 5‐FU are related to the circadian variation in the activity of dihydropyrimidine dehydrogenase (DPD), which is a rate‐limiting enzyme in the pyrimidine catabolic pathway. To optimize the schedule of the CPT‐11 plus 5‐FU combination, we investigated the effect of CPT‐11 on the circadian rhythm of DPD in vivo. In control mice, the DPD mRNA level in the liver was significantly higher at 14:00 than that at 02:00. After intravenous administration of CPT‐11 (30 mg/kg) at 20:00, the circadian rhythm of the DPD mRNA level in the liver was no longer observed 18 h later (14:00), but it was unaffected 6 and 18 h later (at 14:00 and 02:00) when CPT‐11 was given at 08:00. In addition, a dose‐dependent lengthening of the period of the circadian rhythm of DPD was observed for 42 h after intravenous injection of CPT‐11 at 20:00. The levels of DPD protein and activity at 21 h after administration of CPT‐11 (at 17:00) were significantly higher than at 9 h (at 05:00). These results suggest that CPT‐11 may influence the circadian rhythm of DPD at the transcriptional level. Modulation of the circadian rhythm of DPD by CPT‐11 may be a factor in optimizing the combination of 5‐FU and CPT‐11.