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Biomedical subjects

E Raymond

Publications and source records attributed to E Raymond.

At least 91 records · Page 5Linked to original sources
PubMed1997

Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer.

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.

Adenocarcinoma↗
PubMed1997

Preclinical and clinical strategies for development of telomerase and telomere inhibitors.

BACKGROUND: Telomerase is an important enzyme whose activity has been convincingly demonstrated in humans recently. It is required for maintenance of ends of chromosomes (telomeres) during cell division. Since its presence has been selectively demonstrated in dividing cells including tumor cells, it has generated considerable excitement as a potential anti-cancer strategy. DESIGN: In this article, we review the current relevant biology of the enzyme, the challenges encountered in the preclinical phase of target development and the current efforts that focus on telomeres and telomerase as therapeutic targets. We also speculate on the potential toxicities and mechanisms of resistance that may be encountered during use of such therapies.

Animals↗
PubMed1997

Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non-small-cell lung carcinoma.

BACKGROUND: The objectives were to determine the dose-limiting toxicity of topotecan in combination with cisplatin, to describe the principal toxicities, and to define the maximally-tolerated doses of the drugs in previously untreated patients with advanced non-small-cell lung carcinoma. PATIENTS AND METHODS: The study was designed to evaluate escalated doses of topotecan (starting at 0.75 mg/m2/day) as a 30-minute infusion daily for five consecutive days with a fixed clinically-relevant dose of 75 mg/m2 cisplatin given on day 1, every three weeks. RESULTS: Fifteen chemotherapy-naive patients entered the study and 14 were evaluable for toxicity. All 11 patients treated at the first topotecan/cisplatin dose level of 0.75/75 mg/m2, experienced at least one episode of grade 4 neutropenia. For six patients, absolute neutrophil counts were below 500/ml for more than five days, and two of them developed a grade 4 thrombocytopenia. At the next higher topotecan/cisplatin dose level (1.0/75 mg/m2), grade 4 neutropenia lasting longer than five days occurred in all three evaluable patients, including one patient who expired due to a severe neutropenia associated with sepsis. Non-hematologic toxicities, predominantly nausea and vomiting, were mild to moderate in severity and manageable. Four patients had partial responses (30.7%; 95% confidence interval (9%-61%) of relatively short duration. CONCLUSION: Both severe neutropenia and thrombocytopenia precluded dose escalation of topotecan and cisplatin administered on this schedule. In previously untreated patients, the first topotecan/cisplatin dose level (0.75/75 mg/m2), was associated with intolerable myelosuppression, and, therefore, the dose levels evaluated in this study cannot be recommended for subsequent phase II investigations. The high toxicity of this schedule and the recent understanding of the pharmacokinetic interaction between those drugs may encourage the investigation of the alternate sequence of cisplatin after TPT in phase II studies.

Aged↗
PubMed1997

Effects of prolonged versus short-term exposure paclitaxel (Taxol) on human tumor colony-forming units.

Paclitaxel shows a broad clinical activity in ovarian, breast and non-small cell lung cancers. However, controversy remains about the respective effects of doses and schedules in paclitaxel cytotoxicity. This study was conducted to compare the cytotoxic activity of short-term (1 h) versus prolonged exposure (14 days) to paclitaxel in human cancer cells. A soft-agar cloning system assay was used to determine the in vitro effects of 0.025-25.0 microg/ml paclitaxel against cancer cells taken directly from patients. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in positive controls. Among 11 evaluable patients' biopsies, both short- and long-term exposure to paclitaxel had significant concentration-dependent effects on the growth inhibition of human cancer cells. With the 1 h exposure schedule, in vitro responses were observed in 9,18 and 64% of evaluable tumor specimens at final concentrations of 0.25, 2.5 and 25.0 microg/ml, respectively. With the prolonged exposure schedule, concentrations of 0.25, 2.5 and 25.0 microg/ml induced 27, 45 and 91 in vitro response rates, respectively. In those patients' biopsies prolonged exposure to paclitaxel induced significantly more in vitro tumor responses than 1 h administration (p < 0.01). Similar trends were observed in ovarian, breast and non-small cell lung cancers. Our data indicate that the duration of exposure to paclitaxel is an important factor in paclitaxel cytotoxicity in human tumors and suggest that long-term exposure may improve the antitumor activity of paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers.

Oxaliplatin, classical [5-fluorouracil (5-FU)] and non-classical (AG337) thymidylate synthase inhibitors have shown promising activity in the treatment of cancer. This study investigates the cytotoxic effects of oxaliplatin in combination with 5-FU and AG337 in cultured human colon (HT29, CaCo2), breast (MCF-7, MDA-MB-231) and ovarian (2008) cancer cell lines, and their derived counterparts selected for their resistance to 5-FU (HT29-5-FU), doxorubicin (MCF-7mdr) or cisplatin (2008C13). Therapeutic experiments were conducted in mice bearing colon-HT29 xenografts and in the GR hormone-independent mammary carcinoma model. In vitro, oxaliplatin shows potent cytotoxic activity in colon (IC50 from 2.1 +/- 1.1 to 5.9 +/- 1.7 microM), ovarian (IC50 = 10 +/- 1.6 microM) and breast cancer cells (IC50 from 7.4 +/- 2.7 to 17.9 +/- 7.1 microM). Oxaliplatin was a potent inhibitor of DNA synthesis and bound to cellular DNA. Surprisingly, the overall amount of oxaliplatin DNA binding was significantly inferior to that induced by isocytotoxic concentrations of cisplatin in HT29 (p=0.026). In vitro, synergistic antiproliferative effects were observed when oxaliplatin was added to 5-FU and AG337. Those synergistic effects of combinations were maintained in colon HT29-5-FU cancer cells. In vivo, 5-FU increased significantly the antitumor activity of oxaliplatin in HT29 xenografts (p=0.0036), and similarly 5-FU and AG337 increased the activity of oxaliplatin in the GR tumor model (p=0.0012). These data may encourage further clinical investigation of oxaliplatin in combination with classical and non-classical thymidylate synthase inhibitors in the treatment of human cancers.

Antimetabolites, Antineoplastic↗
PubMed1997

Telomerase and telomere inhibitors in preclinical development.

Telomerase is an enzyme required by actively dividing cells to maintain the ends of chromosomes (telomeres). It is present in germline tissue, stem cells and cancer cells, but is repressed in somatic cells. Efforts are underway to exploit this selective expression of telomerase in cancer therapeutics. This review describes the status of telomerase research, which although at present predominantly preclinical, has the potential to enter clinical research.

Journal Article↗
PubMed1997

[Oxaliplatin: the first DACH platinum in clinical practice].

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.

Antineoplastic Agents↗
PubMed1997

[Inhibition of telomeres and telomerase. Seeking for new anticancer drugs].

Human telomeres are guanine-rich regions (TTAGGG) located at the end of chromosomes that protect them against aberrant recombination and protect DNA from exonuclease degradation. Telomeres maintenance is performed by telomerase, a RNA-dependent DNA polymerase. Telomerase is over-expressed in a large number of cancers that have short telomeres whereas it is not expressed in somatic cells that have long telomeres. Therefore, this differential gives a rational for further evaluation of telomerase and telomeres as targets for identification of new anticancer drugs. Current strategies aim to identify new drugs with specific activity against telomerase and telomeres. In this review we will discuss the biological and clinical approaches as well as relevant tumor models for studying the biological effects of telomerase inhibition and telomere targeting in vitro and in vivo.

Animals↗
PubMed1997

Activity of temozolomide against human tumor colony-forming units.

8-Carbamoyl-3-methylimidazo(5,1-d)-1,2,3,5-tetrazin-4(3H)-one (temozolomide) is a new imidazole tetrazinone compound with promising preclinical and clinical activity in nitrosourea-sensitive and -resistant models and manageable toxicity in Phase I and II clinical trials. In this study, we investigated the antiproliferative activity of temozolomide against a large variety of human tumors taken directly from patients in an in vitro soft agar tumor cloning system. Temozolomide was studied using a continuous exposure at final concentrations from 0.1 to 10.0 microM against a total of 222 tumor specimens, of which 101 (45%) were evaluable. A decrease in tumor colony formation was considered significant if survival of colonies treated with temozolomide was </=50% of that in controls. In vitro responses were seen in 9 of 101 [9%; 95% confidence interval (CI), 3-14], 16 of 100 (16%; 95% CI, 8. 5-23), and 35 of 101 (35%; 95% CI, 26-45) tumor specimens at concentrations of 0.1, 1.0, and 10.0 microM, respectively (P < 0. 001). The level of O6-guanine-alkyl-transferase was evaluable in 19 specimens before treatment but did not correlate with a response to temozolomide. At a concentration of 10 microM, a good cytotoxic activity was seen in breast (42%; 95% CI, 15-72), ovarian (36%; 95% CI, 11-69), and non-small cell lung cancers (27%; 95% CI, 6-61). Interestingly, activity was also seen in renal cell carcinomas (50%; 95% CI, 19-81), colon cancers (42%; 95% CI, 15-72), melanomas (33%; 95% CI, 13-59), and some other tumors, including sarcomas and both prostatic and pancreatic carcinomas that are usually considered very resistant to several conventional chemotherapy agents. Moreover, we observed that a subset of tumors that were not sensitive to dacarbazine, carmustine, cisplatin, doxorubicin, 5-fluorouracil, etoposide, and vinblastine were sensitive to temozolomide. These data indicate both that temozolomide is an active drug in vitro against a large variety of human tumors, including some tumors usually resistant to conventional chemotherapy, and that further clinical evaluation is warranted.

Adrenal Gland Neoplasms↗
PubMed1996

[Chemotherapy of colorectal cancers with metastases].

The chemotherapy of metastatic colorectal cancer has demonstrated a symptomatic benefit and a prolongation in survival. The modulation of 5-fluorouracil (5-FU) by leucovorin is the current standard treatment. The best protocols include 5-FU 24 or 48 hour continuous infusion on a weekly or bimonthly schedule. The response rate is about 30%, the median progression-free survival is 6 to 8 months and the median survival 10 to 15 months. The toxicity is moderate. New drugs are available or under evaluation: 5-FU prodrugs, raltitrexed, CPT11, oxaliplatin, trimetrexate. Synergisms with 5-FU allow to consider more effective polychemotherapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Logistic regression model of fotemustine toxicity combining independent phase II studies.

BACKGROUND: To optimize fotemustine chemotherapy, the authors considered how to combine independent Phase II trials to predict the risk of first occurrence of severe toxicity as a function of initial patient characteristics. METHODS: Clinical data from six Phase II trials were collected. Of the 478 patients enrolled 442 (male/female, 259/183; age range, 15-81 years) were evaluable for toxicity (1384 cycles of chemotherapy), including 221 with malignant malignant melanomas, 138 with primary brain tumors, 29 with lung carcinomas, 8 with head and neck carcinomas, and 46 with miscellaneous cancers. The influence of age, sex, performance status, type of tumor, number and location of metastases, and previous treatment by chemotherapy and/or radiotherapy was studied. The logistic regression method was applied to predict occurrence of leukopenia, thrombocytopenia, anemia, digestive tract, and/or hepatic toxicity. RESULTS: Univariate analysis showed that predictive factors for hematologic toxicity were age (> 50 years), type of tumor (brain < melanoma < others), number of metastatic sites (> 3), location of metastases (nonvisceral), and previous chemotherapy. Performance status and previous radiotherapy did not affect the toxicity of fotemustine Nausea and vomiting were predictable based on the type of tumor (head and neck < lung < brain < melanoma < others), the number of metastatic sites (> three) and visceral metastases. Hepatic disorders occurred preferentially in patients with hepatic metastases and more than three metastatic sites. Individual risk of hematologic and hepatic toxicity for patients with melanoma and primary brain tumors was predicted using logistic regression models. CONCLUSIONS: By combining clinical data from independent Phase II trials, the logistic model developed could predict the probability of fotemustine hematologic and hepatic toxicity.

Adolescent↗
PubMed1996

[Chemoprotectors. Mechanisms of action and clinical applications].

Toxicity of chemotherapy remains an important point in the care of patients with malignancies. Since a few years, new compounds without any intrinsic anti tumoral activity have been developed to decrease the toxicity or to enhance the activity of anti-cancer drugs. From those used against the toxic activity of anti-cancer drugs, two classes could be isolated: the chemoprotectors that interact through a specific of chemotherapy in normal cells, and the chemocorrectors that enhance the spontaneous recovery after exposition to cytotoxic drugs. The most widely used chemoprotector remains the 2-mercaptoethanesulfonate (mesna) which protects against the bladder toxicity of ifosfamide and cyclophosphamide. However, two new drugs, amifostine and dextrazoxane have been recently or will be approved in France against the toxicity of cisplatin and anthracyclines, respectively. Mechanism of action and clinical applications of these new drugs in cancer chemotherapy are reviewed.

Amifostine↗
PubMed1996

Agents that target telomerase and telomeres.

Telomeres are guanine-rich regions that are located at the ends of chromosomes and are essential for preventing aberrant recombination and protecting against exonucleolytic DNA degradation. Telomeres are maintained by telomerase, an RNA-dependent DNA polymerase. Because telomerase is known to be expressed in tumor cells, which concurrently have short telomeres, and not in most somatic cells, which usually have long telomeres, telomerase and telomere structures have been recently proposed as attractive targets for the discovery of new anticancer agents. The most exciting current strategies are aimed at specifically designing new drugs that target telomerase or telomeres and new models have been formulated to study the biological effects of inhibitors of telomerase and telomeres both in vitro and in vivo.

Animals↗
PubMed1996

The fluctuation of plasma carotenoid concentrations by phase of the menstrual cycle: a controlled diet study.

This is the first controlled diet study to examine the fluctuation of plasma carotenoids, lipoproteins, and serum hormone concentrations by phase of the menstrual cycle. Nonsmoking, premenopausal women (n = 12) with confirmed ovulatory cycles were given a standard diet with 10 mg total carotenoids/d for two cycles under isoenergetic conditions. Blood was drawn for simultaneous measurement of carotenoids, lipoproteins, and hormones on menses days 1-2, 4-6, 11 through 1 d after the luteinizing hormone surge, and 7-8 d after the surge, representing the menses, early and late follicular, and midluteal phases, respectively. Regression modeling with adjustment for plasma cholesterol concentrations was used to compare mean individual and total plasma carotenoid concentrations by phase of the cycle. Plasma carotenoid concentrations were at their lowest at menses and significantly higher thereafter, except for alpha-carotene. Compared with plasma concentrations at menses, beta-carotene peaked (increased by 9%, P = 0.01) in the late follicular phase. Plasma lutein/zeaxanthin and anhydrolutein concentrations were higher by 8-11% (P < or = 0.006) and by 15-31% (P < or = 0.02), respectively, during the last three phases. Plasma lycopene and phytofluene concentrations peaked (increased by 12%, P = 0.004; and by 21%, P = 0.006, respectively) at the midluteal phase. This cyclic fluctuation may affect the estimation of the plasma carotenoid-disease relation in studies of premenopausal women.

Adult↗
PubMed1996

Synergy between the non-classical thymidylate synthase inhibitor AG337 (Thymitaq) and cisplatin in human colon and ovarian cancer cells.

AG337 is the recent non-classical thymidylate synthase inhibitor with promising activity and manageable toxicity in phase I clinical trials. In this study, we investigated the cytotoxic activity of AG337 alone and in combination with cisplatin in cultured human colon (HT29) and ovarian (2008) cancer cell lines and their derived counterparts selected for their resistance to 5-fluorouracil (5-FU) (HT29-5-FU) and cisplatin (2008C13). We observed that AG337 had potent cytotoxic effects in colon (IC50 = 0.17 MicroM) and ovarian cancer cells (IC50 = 0.65 microM). The cytotoxic activity of AG337 was higher than that of 5-FU in the two models. The Activity of AG337 was not significantly affected in 5-FU-resistant HT29-5-FU colon cancer cells characterized by an amplification of the thymidylate synthase gene (IC50 = 0.27 microM, p = 0.15). Combinations of cisplatin and AG337 exert synergistic activity in both ovarian and colon cancer cells. Interestingly, this synergism was maintained in 5-FU- and cisplatin-resistant cells. Therefore, our data encourage further examination of combinations of AG337 with cisplatin in cancer chemotherapy.

Antimetabolites, Antineoplastic↗
PubMed1996

Protracted continuous infusion of 5-fluorouracil in combination with doxorubicin, vincristine, and oral cyclophosphamide in advanced breast cancer.

Several studies suggest that protracted continuous infusion constitutes an important way to optimize the dose and the efficacy of 5-fluorouracil (5-FU) in metastatic cancer. Eighty-three women aged 27-76 (median age 55) with metastatic breast cancer were treated every 4 weeks with a continuous ambulatory venous infusion of 5-FU 350 mg/m2/day and oral cyclophosphamide 100 mg/m2/day over 15 days. The continuous therapy was associated with a weekly administration of vincristine (0.8 mg/m2) and doxorubicin (15 mg/m2) on day 1, day 8, and day 15. Cycles were repeated every 28 days. Thirty-four patients were treated in first-line metastatic chemotherapy and 49 in second-line. Toxicities included: mucositis (grade > or = 2) 23%, diarrhea (grade > or = 2) 7%, a hand-foot syndrome (grade > or = 2) 9%, alopecia (grade 3) 21%, neurological (grade > or = 2) 4%, grade 3 and 4 leukopenia 29%, and grade 3 and 4 thrombopenia 8%. Heart toxicity was only 3%. Catheter infection was observed in 1 case and 7 patients experienced thrombosis. The overall objective response rate (OR) was 48% and the complete response rate was 23%. The median duration of response was 10 months. The median survival was 16 months. Activity was better in naive than pretreated women (respectively, 55% and 42% of OR, p = 0.21). Analysis of responses according to the metastatic sites shows the pronounced efficacy on soft tissue diseases (skin recurrences 42%, lymph nodes 52%), and also in visceral metastases (hepatic 36%, lung 34%).

Administration, Oral↗
PubMed1996

Effects of PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 fusion protein, on human tumor colony-forming units taken directly from patients.

PIXY321, a granulocyte-macrophage colony-stimulating factor/interleukin 3 (GM-CSF/IL-3) genetically engineered hybrid, has shown greater biological activity in stimulating committed myeloid progenitors than either GM-CSF or IL-3 in vitro, in vivo, and in patients treated with high-dose chemotherapy. However, one concern is that PIXY321 may stimulate the proliferation of malignant cells which have functional GM-CSF or IL-3 receptors. Therefore, using a human tumor cloning assay, we have tested the effects of several concentrations of PIXY321 ranging from 0.1 to 100 ng/ml on tumor cells taken directly from 98 patients with solid tumors and Hodgkin's or non-Hodgkin's lymphomas. Of the 34 evaluable specimens, including 15 breast cancers, 5 ovarian cancers, 5 lung cancers, and 9 lymphomas, none showed stimulation of tumor growth. Interestingly, a significant inhibition of the tumor proliferation was seen in one breast cancer and in one large cell immunoblastic non-Hodgkin's lymphoma after continuous exposure of PIXY321. In conclusion, the use of PIXY321 to reduce myelosuppression after high-dose chemotherapy appears unlikely to result in stimulation of the growth of malignant cells in patients with lymphoma or cancers of the breast, lung, and ovary.

Breast Neoplasms↗