摘要:

STI571 (imatinib mesylate) is an example of the successful development of a targeted agent. Its target is the constitutively active tyrosine kinase (p210bcr–abl) in a hematologic neoplasm, chronic myelogenous leukemia (CML). The results in early clinical trials were remarkable and led to rapid approval by the Food and Drug Administration for clinical use of the STI571 in CML. This article reviews the pre-clinical and clinical development of this agent and also discusses some of the prevailing theories to explain the emerging problem of resistance. Future directions for this drug, possibly directed at other targets, are also discussed.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Insufficient blood supply of rapidly growing tumors leads to the presence of hypoxia, a well-known feature in solid tumors. Hypoxia is known to decrease the efficiency of currently used anti-cancer modalities like surgery, chemotherapy and radiotherapy. Therefore, hypoxia seems to be a major limitation in current anti-cancer therapy. The use of non-pathogenic clostridia to deliver toxic agents to the tumor cells takes advantage of this unique physiology. These strictly anerobic, Gram-positive, spore-forming bacteria give, after systemic administration, a selective colonization of hypoxic/necrotic areas within the tumor. Moreover, they can be genetically modified to secrete therapeutic proteins like cytosine deaminase or tumor necrosis factor-&agr;. The specificity of this protein delivery system can be further increased when expression is controlled by the use of a radio-inducible promoter, leading to increased spatial and temporal regulation of protein expression. This approach of bacterial vector systems to target protein expression to the tumor can be considered very safe since bacteria can be eliminated at any moment by the addition of proper antibiotics. TheClostridium-based delivery system thus presents an alternative therapeutic modality to deliver anti-tumor agents specifically to the tumor site. This high selectivity offers a major advantage in comparison with the classical gene therapy systems.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Epidemiological and experimental studies have demonstrated the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention of human cancers. NSAIDs block endogenous prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymatic activity. COX-2, a key isoenzyme in conversion of arachidonic acid to prostaglandins, is inducible by various agents such as growth factors and tumor promoters, and is frequently overexpressed in various tumors. The contribution of COX-2 to carcinogenesis and the malignant phenotype of tumor cells has been thought to be related to its abilities to (i) increase production of prostaglandins, (ii) convert procarcinogens to carcinogens, (iii) inhibit apoptosis, (iv) promote angiogenesis, (v) modulate inflammation and immune function, and (vi) increase tumor cell invasiveness, although some studies indicated that NSAIDs have COX-2-independent effects. A number of clinical trials using COX-2 inhibitors are in progress, and the results from these studies will increase our understanding of COX-2 inhibition in both cancer treatment and prevention. The combination of COX-2 inhibitors with radiation or other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Recent progress in the treatment and prevention of cancers of the colon, esophagus, lung, bladder, breast and prostate with NSAIDs, especially COX-2 inhibitors, is also discussed.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The systemic exposure to the anticancer agent irinotecan (CPT-11) and its active metabolite SN-38 were 79 and 92% reduced, respectively, relative to literature data, by concomitant phenytoin therapy. This finding suggests that increased doses of CPT-11 should be given to patients treated simultaneously with these drugs, to achieve adequate levels of SN-38.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Fotemustine (Muphoran®, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol®, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC50of fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of fotemustine as a significant decrease in IC50was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation ofO6-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Bovine seminal ribonuclease (BS-RNase) is an antitumoral active enzyme exhibiting specific antitumoral action against a number of different cancer cell lines. However, its systemic use is limited by its pharmacokinetic properties and antigenicity. Therefore, it was conjugated to polyethylene glycol (PEG) chains to overcome these problems. Measurement of aspermatogenic effects of the preparation after s.c. injection and injection into the scrotum was chosen as a model for the distribution of the enzyme in the body mediated by the linkage to PEG chains. Additionally, the antigenicity of BS-RNase coupled to PEG chains (BS-RNase–PEG) was compared to that of free BS-RNase, as antigenicity is known to be one of the main obstacles in the use of protein-based drugs. BS-RNase–PEG caused aspermatogenic effects after systemic administration to mice in very low concentrations at which free BS-RNase is not effective. Moreover, BS-RNase possessed a very low antigenicity as long as it was coupled to the PEG chains. In order to investigate the antitumoral efficacy of BS-RNase–PEGin vivo, preliminary experiments on the effect of the conjugate on neuroblastoma growth in mice were performed in a UKF-NB-3 xeno-transplantate model, demonstrating a drastically increased anti-tumoral activity of the conjugate compared to the free enzyme.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We sought to determine whether gemcitabine, a new pyrimidine antimetabolite, could inhibit the growth of human osteosarcoma cells (OS)in vitroandin vivo. Four human OS cell lines (MG-63, TE-85, SAOS-2 and SAOS-LM7) were used to assess the activity of the drugin vitro. Gemcitabine caused growth inhibition and cell death in all four cell lines as measured using the MTT and colony-forming assays (IC50 = 6.5 nM–9 μM and 7–14 nM, respectively). Using our newly developed human SAOS-LM7 OS lung metastasis mouse model, we assessed thein vivoactivity of gemcitabine given i.p. and intranasally (i.n.). Mice were treated twice weekly for 3 weeks and then once weekly for 3 weeks using either i.p. or i.n. gemcitabine starting 4 weeks after tumor cell injection. The i.p. injection, at 120 mg/kg, resulted in a decrease in lung weights and the size of the nodules. However, no significant reduction in the number of metastatic nodules was seen (control median: >200 versus gemcitabine median: 150,p = 0.084). In contrast, the number of lung metastases was significantly decreased in mice that received i.n. gemcitabine at 15 (median: 1; range: 0–115,p<0.005) and 12 mg/kg (median: 41; range: 7–163,p = 0.005) when compared with control mice (median: >200). Intranasal therapy is a non-invasive method of drug delivery and has the advantage of targeting the lung, resulting in a higher drug concentration in the tumor area. In our study, i.n. instillation of gemcitabine inhibited the growth of lung metastases at an 8- to 10-fold lower dose than that used i.p. and appeared to be more effective in eradicating OS lung nodules. Because the lung is the most common site of OS metastasis, our data suggest that i.n. gemcitabine may be a novel therapeutic approach in the treatment of OS lung metastases.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We undertook a phase II trial in 17 patients with malignant glioma and large measurable disease to assess response rate and survival with pre-irradiation chemotherapy, using higher doses than standard, trying to improve the outcome. Patients characteristics were: male/female 10/7, age 49 (range 23–59), median Karnofsky index 90% (range 70–100), glioblastoma multiforme/anaplastic astrocytoma 14/3. Treatment consisted of 2 cycles of carboplatin 200 mg/m2 days 1–3 (or AUC×8, total dose) plus cyclophosphamide 1000 mg/m2 days 1–3. One partial response (6.5%) and two stabilizations (13.5%) were observed after pre-irradiation chemotherapy. Twelve out of 15 patients (80%) progressed after chemotherapy. Median survival time was 7.6 months and the survival at 1 year was 33%. Main toxicity was hematologic in the first cycle: neutropenia grade 4 in 100%; thrombocytopenia grade 4 in 73% and grade 3 in 27%; anemia grade 3 in 7%; in the second cycle: neutropenia and thrombocytopenia grade 4 in 100% and anemia grade 3 in 50%). No toxic death was related to treatment. This regimen showed limited activity in malignant glioma with large residual disease after surgery or biopsy.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The camptothecin derivative 9-nitrocamptothecin (9-NC) has demonstrated clinical activity in patients with ovarian and pancreatic carcinomas. Preclinical studies have shown promising activity of 9-NC for melanoma. We have thus conducted a phase II clinical trial of 9-NC for patients with metastatic cutaneous and uveal melanoma. Twenty-eight patients were enrolled in the trial, with diagnoses evenly divided between the two types of melanoma. 9-NC was administered orally at a starting dose of 1.5 mg/m2/day for 5 consecutive days of each week. No complete or partial responses were observed. Stabilization of disease was achieved in four individuals (15%) for durations of 3, 4, 6 and 8 months. Hematologic toxicity was moderate. Gastrointestinal side effects were common with 43% of the patients experiencing grade 3 or 4 diarrhea and 18% reporting grade 3 or 4 vomiting. In contrast to other 9-NC clinical trials, no patients developed chemical cystitis with gross hematuria. We conclude that, in keeping with the general chemoresistance of melanoma, 9-NC at the dose and schedule studied in this trial is significantly toxic and is not active for metastatic melanoma of cutaneous or uveal origin.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Chemotherapy for recurrent ovarian carcinoma (ROC) produces response rates of 10–80% depending on the prevalence of platinum resistance. Most patients relapse within 1 year and median progression-free survival is generally no more than 6 months. Newly developed ATP chemosensitivity assays (ATP-TCA) offer the opportunity for individualized therapy and have shown promising results compared to standard regimens. We report on an unusual case of long-term survival in a patient with stage III c ovarian cancer failing postoperative platinum-based high-dose treatment who subsequently underwent repeated chemotherapy over a period of 4 years. The chemotherapy protocol was selected by pretherapeuticex vivoATP-based chemosensitivity testing of autologous tumor tissue. To our knowledge, this is one of the few cases of ROC in which partial remissions using conventionally dosed chemotherapy were achieved repeatedly despite a unfavorable relapse-free interval after high-dose chemotherapy for primary disease. We conclude that ATP-TCA-directed chemotherapy for ROC can select active and tolerable regimens even in difficult therapeutic situations in which no standards recommendation exists.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID