摘要:

5-Fluorouracil (5-FU) has been available for over 40 years and has been used in a wide variety of different regimens for the treatment of advanced colorectal cancer, a malignancy with a poor prognosis that is common in industrialized countries. However, despite numerous clinical trials in which 5-FU has been used alone and in combination with a variety of modulating agents [chiefly leucovorin (LV)], and has been administered by bolus injection and i.v. infusion, the optimal regimen for the management of advanced colorectal cancer remains unclear, and there are notable national and international variations in clinical practice. The toxicity of 5-FU also remains an obstacle to the achievement of overall clinical benefit in many patients. The introduction of novel chemotherapeutic agents may make it necessary to reassess the place of 5-FU in the treatment of advanced colorectal cancer. This article debates these issues with a review of clinical trials of 5-FU, and concludes that the future lies in the utilization of novel and established agents in combinations that may significantly improve outcomes, rather than in continuing experimentation with various schedules of 5-FU and LV.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The effect of biochemical modulation of weekly high-dose 5-fluorouracil (5-FU) 24 h infusion by leucovorin (LV) in the treatment of 39 consecutive patients with advanced gastric cancer without prior chemotherapy from October 1996 to August 1997 was examined. There were 21 male and 18 female patients with a median age of 56 years. The regimen consisted of 5-FU 2600 mg/m2and LV 150 mg administered by 24 h infusion weekly for 6 weeks followed by a 2 week break. The treatment was repeated every 8 weeks until disease progression, patient refusal or unacceptable toxicity. Placement of a central vascular device and a portable external infusion pump was required in all patients and was used for outpatient treatment. The response to treatment was evaluated every 8 weeks. A total of 395 chemotherapy treatments were given with a mean of 10 (2–24). This response rate was: 33% (12 of 36) partial response (PR) rate, 33% (12 of 36) stable disease (SD) and 33% (12 of 36) progressive disease (PD). In general, the toxicity was mild but two toxic deaths occurred, one due to neutropenic sepsis and the other due to hyperammonemia. The median time to progression was 4 months. The overall median survival was 7 months. The survivals of the PR, SD and PD were 12, 8 and 5 months, respectively. This regimen showed a modest activity against gastric cancer with acceptable toxicity. Weekly 24 h infusion of high-dose 5-FU with LV in an outpatient setting for patients with gastric cancer is feasible and deserves further study as a basis for combination therapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40–8757 and to determine the dose-limiting toxicity (DLT) of Ro 40–8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40–8757 P.O. day 1–21, cisplatin 100 mg/m2i.v. on day 2 and VP-16 100 mg/m2i.v. on day 2–4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40–8757 ranged from 84 mg/m2once daily to 42 mg/m2thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40–8757 appears to be feasible at a dose schedule of 28 mg/m2tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Preclinical and clinical data have suggested antitumor efficacy in squamous cell carcinoma (SCC) of interferon (IFN)-α and 13-cis-retinoic acid (13-c-RA) as single agent with greater activity in combination. Cisplatin was added to potentiate activity. Twenty-three patients with pretreated advanced or metastatic head and neck squamous cell carcinoma were given a combination of IFN-α (6 × 106U/day, 84 days s.c.), 13-c-RA (1 mg/kg/day, 84 days) and cisplatin (40 mg/kg/day, day 1, 28 and 56). Seventeen patients had discontinuation of treatment and three patients received overall treatment without dose reduction. Hematological toxicity was more frequent; only three patients experiencing grade 3 or higher extra-hematological toxicity. Four out of 14 evaluable patients were in response, with one in complete pathological response. Median duration of response was 6 months with a 9 month median survival. Association of IFN-α, 13-c-RA and cisplatin induces modest but definite antitumor activity with moderate and manageable toxicity. Further studies of different combination modality therapy with chemotherapy and differentiating agents need to be performed in less pretreated patients.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

9-Nitrocamptothecin (9-NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. A phase II study was performed in patients with heavily refractory ovarian, tubal or peritoneal cancer (median number of previous chemotherapy regimens >3) to determine the activity of a daily oral dose of 9-NC. 9-NC dose was 1.5 mg/m2/day for four consecutive days every week. Increments of 0.25 mg/day were authorized in patients without significant side effects. Of 29 evaluable patients, a 7% remission rate was observed. Thirty-four percent of patients had stable disease. The median survival was 8 months. Toxicity was evaluated in 31 patients. Grade 3 or 4 hematologic toxicity consisted of anemia in 10 patients (32%), neutropenia in eight (26%) and thrombocytopenia in three (10%). Grade ≥2 non-hematologic toxic effects were nausea and vomiting in 26 (84%), diarrhea in 12 (39%), weight loss in seven (22%), chemical cystitis in six (19%) and neutropenic sepsis in six (19%). 9-NC was tolerated for sustained periods of time in some patients (up to 47 weeks). The observed 8-month survival in such a refractory patient population is noteworthy. Further clinical research of prolonged exposure to less toxic analogs of 9-NC is warranted.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p< 0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 ± 85 versus 499 ± 50, p=0.004 and 5-FU: 5393 ± 962 versus 5136 ±963,p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164±46 versus 151±52,p=0.018 and 5-FU: 1652 ±478 versus 1553 ±535, p < 0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p < 0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

This study evaluated the toxicity and efficacy of topical topitriol (calcitriol, 1,25-dihydroxyvitamin D3) to prevent chemotherapy-induced alopecia (CIA). Patients with breast cancer scheduled to receive FAC chemotherapy (5-fluorouracil, adriamycin and cyclophosphamide) were eligible for the study. Initially, the first six patients were randomized in a double-blind fashion to have received topitriol or placebo with all subsequent patients being treated with topitriol. Topitriol cream (0.0025 or 0.005%; 25 and 50 μg/g concentration) was administered topically twice a day. Three different doses and schedules of administration were evaluated including: 500 and 1000 /μg daily for 7 days prior to chemotherapy, and 2000 μg daily for 5 days prior and 5 days post-chemotherapy. Fourteen patients were treated (12 with topitriol and two with placebo) at three different dose levels. All patients developed grade 2 alopecia between day 20 and 30 after chemotherapy, demonstrating the lack of efficacy of topical topitriol on this schedule of administration to prevent CIA. Eight patients exposed to topitriol developed a toxic maculopapular dermatitis in areas exposed to the drug. In conclusion, topical topitriol at the doses and schedules evaluated in this trial was ineffective to prevent CIA and induced a local dermatitis in areas exposed to the drug.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Paclitaxel (Taxol) is known to act by polymerizing and stabilizing microtubules. In spite of a known target, the existence of additional targets is suggested by a poor understanding of the mechanism(s) underlying eventual cell death by paclitaxel and by the drug's high efficacy, as compared to other spindle poisons. Based on the enhanced sensitivity of a mutant DNA double-strand break repair- deficient Chinese hamster ovary cell line to paclitaxel as well as to various topoisomerase (Topo) II poisons, it was hypothesized that paclitaxel, in addition to having an effect on microtubules, may also alter the activity of Topo II. This study demonstrates the unique,in vitroeffects of paclitaxel on Topo II activity as investigated by monitoring the decatenation of kinetoplast DNA and relaxation of super-coiled plasmid DNA by Topo II. Unlike classical anti-topoisomerase drugs, low concentrations of paclitaxel (0.02–500 nM) stimulated Topo II catalytic activity, while higher concentrations over 5 μM inhibited the activity of Topo II. Furthermore, these effects of paclitaxel appear to be mediated through a direct interaction of paclitaxel with Topo II rather than an interaction with ONA or DNA-Topo II complexes. Collectively, the evidence presented suggests the existence of an atypical interaction between Topo II and paclitaxel that may disrupt the normal functioning of the enzyme.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Based on the rationale of a preferred albumin uptake by tumors, conjugates comprising of rat serum albumin (RSA) as a drug carrier and of methotrexate (MTX) as chemotherapeutic drug were prepared. For a comparative study of MTX-RSA and MTX we chose a slow growing Dunning R3327 HI prostate cancer model. In a radiopharmacologic study blood kinetics and the tumor and organ distribution pattern of residualizingly labeled MTX-RSA were determined, and were found to be similar to that of residualizingly labeled RSA. The MTD was established for Copenhagen rats at a total four injections of 2 mg/kg MTX or MTX-RSA administered at days 0, 4, 8 and 12. Tumor volume measurements and tumor removal showed a small non-significant growth delay in the MTX treatment group, suggesting MTX resistance for the Dunning R3327 HI prostate carcinoma. In contrast, treatment with MTX-RSA resulted in a significant (50%) growth inhibition of the Dunning R3327 HI tumor. The cellular mechanisms responsible for MTX resistance in Dunning HI tumor cells is not known. The improved therapeutic effects seen during MTX-RSA treatment in this slow growing adenocarcinoma might be a result of prolonged tumor exposure time and an altered cellular uptake by a lysosomal route. MTX-albumin conjugates have shown antitumor activity exceeding that of MTX in several tumor xenografts in nude mice, including human prostate cancer. The recently initiated clinical development of MTX-human serum albumin will be continued and cancer of the prostate will be included as a potential target tumor during further clinical phase II testing.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Gamma linoleic acid (GLA) salts may exert a direct antiproliferative activity on tumor cells. The cytotoxicity is linked to the generation of conjugated dienes, peroxyl radicals and superoxide radicals. Lithium gammalinolenate (LiGLA) and meglumine gammalinolenate (MeGLA) have been recently developed for enhancing the water solubility of these compounds. MeGLA or LiGLA (10−5to 10−4mol/l) and fotemustine (Fote) (2 × 10−6to 2 × 10−4mol/l) were applied, alone or in combination, for up to 9 days to two human glioblastoma cell lines A172 and U373MG. Fote was applied first followed by LiGLA and/or MeGLA. Cytotoxicity was evaluated by the MTT test, and the effects of drug combinations were analyzed by the isobolographic representation according to the Chou and Talalay method (combination indexes). For both GLA salts, cytotoxicity was manifested after 4 days of cell exposure and with very sharp dose-response curves. Comparison of IC50values indicated that MeGLA was more active than LiGLA. There was a constant reduction in IC50values following an increase in exposure time for A172 cells: between 4 and 9 days of cell exposure, IC50changed from 73 to 46 μM for LiGLA and from 49 to 31 μM for MeGLA (p< 0.05). With U373MG cells, there was no influence of exposure duration on IC50values. Combination index values indicated that association between Fote and GLA salts globally resulted in slightly antagonistic effects. These results may be useful for further development of GLA salts at the clinical level.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID