摘要:

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by many tumors, and mediates growth, motility and protection from apoptosis. Inhibition of IGF1R expression or function has been shown to block tumor growth and metastasis, and enhance sensitivity to cytotoxic drugs and irradiation. Thus the IGF1R is a highly promising anti-cancer treatment target. This review describes approaches to target the IGF1R using antibodies, small molecule inhibitors of the IGF1R tyrosine kinase, and molecular agents such as antisense and small interfering RNAs. Problems for the clinical introduction of this approach may include toxicity due to normal tissue IGF1R expression and cross-reactivity with the insulin receptor. The next few years will see clinical trials of IGF1R targeting, which offers genuine potential to inhibit tumor growth and chemoresistance in patients with cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Studies of the mechanism of action of a shikonin derivative, &bgr;-hydroxyisovalerylshikonin (&bgr;-HIVS), have revealed that &bgr;-HIVS inhibits the protein tyrosine kinase (PTK) activities of the receptor for epidermal growth factor and v-Src. In this review, we compare the characteristics of the inhibition of PTK activity by &bgr;-HIVS with those of other inhibitors of PTKs. The chemical structure of &bgr;-HIVS is completely different from that of ATP and it does not resemble any of the PTK inhibitors reported to date, except that it includes the benzilidene moiety. In contrast to most PTK inhibitors, the mechanism of inhibition by &bgr;-HIVS is non-competitive with respect to ATP, but competitive with respect to its peptide substrate. This feature of the mechanism of inhibition of PTK by &bgr;-HIVS suggests that it might be useful in a clinical setting with other PTK inhibitors. When Bcr–Abl-positive, human leukemia K562 cells were treated simultaneously with &bgr;-HIVS and STI571 (Gleevec), these compounds had a synergistic effect on both the induction of apoptosis in K562 cells and the inhibition of the phosphorylation activity of PTK, probably because the mechanism of interference with phosphorylation by &bgr;-HIVS and the binding site of &bgr;-HIVS are different from those of STI571.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism, has been a key target for the development of novel oral fluoropyrimidines. DPD-inhibiting oral fluoropyrimidines showing promise in early clinical studies included UFT (the 5-FU prodrug, tegafur, plus the DPD substrate, uracil), eniluracil (an irreversible DPD inhibitor that improves the oral bioavailability of 5-FU) and S-1 (tegafur plus a reversible DPD inhibitor, 5-chloro-2,4-dihydroxypyridine, and oxonic acid). However, results from phase II/III trials evaluating these agents as first-line therapy for metastatic colorectal cancer have been disappointing. Although DPD-inhibiting oral fluoropyrimidines have some activity in colorectal cancer and oral administration provides significant convenience advantages, the inferior efficacy of UFT/leucovorin and eniluracil/5-FU versus 5-FU/leucovorin in phase III trials does not support the use of these compounds. A feasible regimen for the phase III development of S-1 outside Japan has not been defined. Thus the DPD-inhibiting oral fluoropyrimidines have failed to fulfill their early promise: clinical data indicate that none of these compounds is likely to improve outcomes for patients with metastatic colorectal cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This article reviews the available data regarding the activity of second-line chemotherapy following 5-fluorouracil (5-FU), irinotecan (CPT-11) or oxaliplatin (OXA) alone or in combination. Studies undertaken in this setting, published both as full papers and in abstract form, were critically analyzed. The main conclusion is that clinical research for second and subsequent lines of treatment in advanced colon cancer (ACC) clearly needs to be optimized. A large number of small, non-randomized phase II trials have been reported without definitive conclusions. Efficient conduct of a limited number of high-quality randomized phase II trials with validation of promising regimens via phase III studies seems a preferable approach. This would not only accelerate the evaluation of new therapeutic options, but also, and more importantly, limit the number of patients receiving suboptimal treatments. The responsibility of this indispensable and urgent task lies with all researchers in this field and their partners in the pharmaceutical industry. One means to implement this approach is through strict selection of studies to be both presented and published, encouraging the spread of information provided by statistically well-designed and well-conducted trials that will eventually lead to the definition of the best standard of care for ACC patients. The conduct of repetitive phase II trials that test minor variations in dose and schedule, while commonplace, does little to advance the field.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Chemosensitivity testing is considered by some to be a useful method for predicting drug sensitivity of tumor tissues after surgery for gastrointestinal cancer. Although survival benefit is not fully established, several chemosensitivity testing methods have been used clinically, both in the selection of adjuvant therapy and in the treatment of metastatic disease. Chemosensitivity testing is used not only for determination of drug resistance, but also for determination of drug sensitivity conferring a potential survival benefit. Previous retrospective correlation studies showed survival of patients treated with a ‘tested’ drug to be superior to that of patients treated with a standard drug, but the clinical benefit of chemosensitivity testing in comparison to surgical therapy alone or standard chemotherapy has not been documented in a randomized controlled trial. The clinical usefulness of individualized versus standard therapy needs to be determined. Here we discuss the potential survival benefit and current limitations of chemosensitivity testing in patients with gastrointestinal cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The development of colony-stimulating factors (CSFs) has provided clinicians with a valuable tool for proactive management of chemotherapy-induced neutropenia. However, clinicians are also presented with the challenge of appropriately targeting this treatment to patients at serious risk of neutropenic complications, while maintaining an economic approach to prescribing. This article discusses the seriousness of chemotherapy-induced neutropenia and reviews current approaches to the management of this condition. Febrile neutropenia risk models, new therapy options and international guidelines for the use of CSFs are also discussed.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We reviewed the records of 25 colon cancer patients consecutively treated with an oxaliplatin-containing regimen. We differentiated between hypersensitivity reactions and pain reactions due to oxaliplatin. The patients did not receive preventive pre-medication. Four patients underwent an adverse reaction. Three patients fulfilled the criteria of a hypersensitivity reaction with tachycardia, chills and hyperhidrosis. In addition, two patients suffered from severe abdominal and chest pain. Reactions occurred during or shortly after the oxaliplatin infusion. All patients recovered under symptomatic therapy. After reacting for the first time, pre-medication was applied prior to the oxaliplatin infusion. However, due to further reactions, the treatment protocol had to be changed in all cases into a regimen not containing oxaliplatin. We conclude that adverse reactions are relatively frequent toxic side-effects of oxaliplatin, mainly in heavily pre-treated patients. Pre-medication was ineffective in preventing further reactions and consequently the treatment regimen had to be changed in all cases.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We report on three cases of long-term dialysis patients with gynecological malignancies who were successfully treated with chemotherapy. Two epithelial ovarian carcinoma patients were treated with a single agent, carboplatin (100–200 mg/m2). One recurrent endometrial carcinoma patient was treated with carboplatin (200 mg/m2) and paclitaxel (135 mg/m2). Hemodialysis was started 2 h after the carboplatin infusion and lasted 4 h in all three cases. All patients tolerated these therapies without significant myelosuppression or severe side-effects. Our findings suggest these regimens are feasible, and the combination of paclitaxel and carboplatin is effective chemotherapy when administered to long-term hemodialysis patients with recurrent endometrial carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This phase II trial assessed the cardiovascular safety and tolerability of high-dose granisetron for the treatment of nausea and vomiting in cancer patients undergoing emetogenic chemotherapy. Forty-one patients were given 30-min infusions of granisetron, 40 or 120 μg/kg i.v., as either a single dose or as split doses, at 6-h intervals. Subsequently, patients had the option of the alternative dosing regimen or to return to conventional antiemetic therapy. Patients were monitored for 24 h following the first granisetron infusion. Electrocardiogram (ECG; lead II and Holter monitoring) measurements were made during the study and blood samples for pharmacokinetic analysis were taken at regular intervals for 48 h after the start of the first granisetron infusion. During the first chemotherapy session, granisetron was administered as: (i) bolus doses of 80 μg/kg (n=3) and 120 μg/kg (n=19) or (ii) split doses of 2×40 μg/kg (n=1) and 3×40 μg/kg (n=18). Crossover therapy was administered to 22 patients, with granisetron doses of 120 μg/kg (n=12), 2×40 μg/kg (n=1) and 3×40 μg/kg (n=9). We conclude that supra-therapeutic doses up to 120 μg/kg granisetron had no clinically significant effect on ECG, pulse rate or blood pressure. The treatment was well tolerated with no significant changes in biochemistry or hematological parameters.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m25-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7–39%). Nausea and vomiting presented in two patients (8%; 95% CI 1–25%). The response rate of 26 patients can be summarized as follows: partial remission:n=7 (27%; 95% CI 12–48%); stable disease:n=9 (35%; 95% CI 17–56%) and progressive disease:n=10 (38%; 95% CI 20–59%). The median progression-free survival (n=26) was 5.8 months (range 3–13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2–24) and counted from the start of first-line treatment (n=26) was 23 months (range 10–66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID