Effect of the Hsp90 modulators on the heat-shock response in eukaryotic cells.

The possible role of the heat-shock protein 90 (Hsp90) complex on the heat-shock (HS) response in yeast using the Hsp90 inhibitors geldanamycin (GA) and 17-allylamino-17-demethoxygeldanamycin (AAG), and prednisolone and 17beta-estradiol as modulators was investigated. Following long- or short-term administration of the drugs, either alone or in combination, the response was determined as cell viability and growth after exposure to HS. Upon short-term preconditioning, both Hsp90 inhibitors conferred cycloheximide-dependent thermal resistance to the yeast cultures, while upon long-term treatment the induction of thermotolerance was confined only to AAG. Co-administration of prednisolone or 17beta-estradiol failed to significantly alter the response to Hsp90 inhibitors. However, since short-term incubation with prednisolone alone induced thermotolerance, increased the budding cell fraction and tended to reduce the adaptive response to GA, its effect on GA-induced thermotolerance is not yet explained. Generally, GA and AAG showed a comparable short-term action but a different long-term effect on the HS response in yeast; this response was not related to any regulation by prednisolone or 17beta-estradiol (while 17beta-estradiol was unable to modify the response, the action of prednisolone in both the stress response and the cell cycle was equivocal).

Irinotecan plus gemcitabine vs irinotecan for the second-line treatment of patients with advanced non-small-cell lung cancer pretreated with docetaxel and cisplatin: a multicentre, randomised, phase II study.

To compare irinotecan (CPT-11)+gemcitabine vs CPT-11 alone as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC) progressing after docetaxel-cisplatinum-based therapy. A total of 147 evaluable, pretreated patients, with NSCLC, received either gemcitabine (1000 mg m(-2), days 1 and 8)+CPT-11 (300 mg m(-2), day 8) (Group A, n=76) or CPT-11 (300 mg m(-2), day 1) (Group B, n=71), every 3 weeks. All patients were evaluable for response and toxicity. The objective response rate was 18.4% (95% CI: 9.71-27.14%) and 4.2% (95% CI: 0-8.90%) (P=0.009) for groups A and B, respectively. No significant differences between the two groups in terms of the median duration of response, time to tumour progression, overall survival and 1-year survival were observed. The CPT-11/gemcitabine regimen significantly improved the patients' quality of life ('general mood today' (P=0.014), 'coughing' (P=0.003) and 'intensity of symptoms' (P=0.034)) compared with CPT-11. More cycles had to be delayed (P=0.001) and required prophylactic growth factor support (P=0.001) in Group A than B. Three (3.9%) patients in Group A and eight (11.3%) in Group B developed febrile neutropenia (P=0.09); one patient died of sepsis in each group. Three additional (Group A, n=1; Group B, n=2) treatment-related deaths were observed. Grade 3-4 haematologic toxicity was comparable in the two groups except anaemia (P=0.03 in favour of CPT-11). Other nonhaematologic toxicities were mild and similar in the two groups. CPT-11+gemcitabine resulted in a higher response rate and better control of disease-related symptoms than CPT-11 alone, but without any improvement in the overall survival.

Salvage treatment of metastatic breast cancer with docetaxel and carboplatin. A multicenter phase II trial.

OBJECTIVES: To evaluate the efficacy and safety of docetaxel in combination with carboplatin as salvage treatment in women with metastatic breast cancer (MBC). PATIENTS AND METHODS: Chemotherapy-pretreated women with MBC were treated with docetaxel 75 mg/m(2) as 1-hour i.v. infusion followed by carboplatin AUC 6 mg/ml.min, using the Calvert's formula, as 30-min i.v. infusion. Cycles were repeated on an outpatient basis every 3 weeks. RESULTS: Thirty-six patients received a total of 210 chemotherapy cycles (median 6 cycles/patient). All but one patient had previously received anthracyclines for the treatment of metastatic disease and half of the patients had failed to respond to front-line treatment. Twenty-eight (78%) patients had visceral disease. On an intention-to-treat analysis there were three (8%) complete and 19 (53%) partial responses for an overall response rate of 61% (95% CI: 45.2-77.0%). The response rate was 44% (2 CRs, 6 PRs) among 18 patients who had progressive or stable disease as best response to front-line treatment. The median duration of response was 8 months, the median time to tumor progression 10 months, and the probability of 1-year survival 66%. Grade 3-4 neutropenia was the main hematologic toxicity occurring in 16 (45%) patients or 36 (17%) cycles. Seven (19%) patients developed 8 (4%) febrile neutropenic episodes. Grade 3 thrombocytopenia occurred in 4 (11%) patients or 6 (3%) cycles. Non-hematologic toxicity was generally mild. G-CSF was used in 19 (53%) patients or 134 (64%) cycles. There was one sudden death possibly related to the treatment. CONCLUSION: The docetaxel-carboplatin combination is an active outpatient salvage regimen for the treatment of women with MBC relapsing or not responding to anthracycline-based front-line therapy.

Induction of morphological alterations by antineoplastic agents in yeast.

Saccharomyces cerevisiae was used as an alternative experimental model in order to investigate the effects of antineoplastic agents on eukaryotic cells. After being exposed to the most common clinically used antineoplastic agents, yeast cells were examined under the light microscope. Folate and pyrimidine antagonists, platinum derivatives, mitomycin C, actinomycin D and bleomycin induced alterations in yeast cellular morphology, which were not observed following treatment with drugs belonging to any category other than the antineoplastics, leading to the suggestion that these alterations could potentially be used as an experimental tool in pre-screening for new chemotherapeutic leads.

Effects of chromatin function inhibitors on yeast whole cells and spheroplasts.

Saccharomyces cerevisiae has long been used as an alternative experimental model in the study of cancer and anticancer drug action. Although this simple eukaryote has provided useful information, its value as an experimental model is often controversial due to the presence of the cell wall -- a cellular structure which is absent in higher eukaryotes. The aim of this study was to investigate the possible involvement of the cell wall in the ineffectiveness of some anticancer drugs in yeast, by enzymatic removal of the cell wall. The effects of exposing whole-cell cultures and spheroplasts to chromatin function inhibitors for 22 hours were investigated. Vinblastine, etoposide and paclitaxel had no cytotoxic effects on whole-cell cultures either with or without the addition of verapamil. The growth profiles of yeast spheroplasts following drug exposure were similar to those observed in whole cells. These data demonstrate that the resistance of the lower eukaryote to these drugs was not overcome by the enzymatic removal of the cell wall.