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Biomedical subjects

David J Kerr

Publications and source records attributed to David J Kerr.

At least 19 recordsLinked to original sources
PubMed2004

Virus-directed enzyme prodrug therapy: intratumoral administration of a replication-deficient adenovirus encoding nitroreductase to patients with resectable liver cancer.

PURPOSE: Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. PATIENTS AND METHODS: Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. RESULTS: Eighteen patients were treated with escalating doses of CTL102 (range, 10(8)-5 x 10(11) virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. CONCLUSION: Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 x 10(11) virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

Adenoviridae↗
PubMed2004

A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.

BACKGROUND: The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results. METHODS: In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation. RESULTS: The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors. CONCLUSIONS: Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Aged↗
PubMed2004

Nitroreductase: a prodrug-activating enzyme for cancer gene therapy.

1. The prodrug CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) is activated by Escherichia coli nitroreductase (NTR) to a potent DNA-crosslinking agent. 2. Virus-mediated expression of NTR in tumour cells sensitizes them to CB1954 in vitro and in vivo, providing the basis for a strategy of cancer gene therapy. 3. A phase I trial of CB1954 in cancer patients has been completed, documenting the pharmacokinetics and establishing an acceptable dose. Subsequent trials of the replication-defective adenovirus CTL102 in patients with resectable tumours have documented expression of NTR in injected colorectal liver metastases, hepatocellular carcinoma, head and neck cancer and prostate cancer. Trials combining CTL102 and CB1954 are underway. 4. An oncolytic (replication-competent) adenovirus vector allowed increased expression of NTR in vitro and in a mouse tumour model, resulting in a greater reduction in tumour growth when combined with CB1954 treatment. 5. Alternative prodrugs may eventually prove superior to CB1954; a nitroaryl phosphoramide mustard prodrug activated by NTR shows a greater therapeutic index than CB1954 in a human ovarian carcinoma. 6. The crystal structure of NTR provided the basis for site-directed mutagenesis, which has identified a number of mutants with improved kinetics of CB1954 activation. These can provide improved cell sensitization to CB1954. Combinations of these are being tested. 7. The basis for a positive selection for improved NTR variants has been demonstrated.

Animals↗
PubMed2003

Immune enhancement of nitroreductase-induced cytotoxicity: studies using a bicistronic adenovirus vector.

The nitroreductase (NR)/CB1954 enzyme prodrug system has given promising results in preclinical studies and is currently being assessed in phase I clinical trials. It is well established that there is an immune component to the bystander effect observed with other systems such as thymidine kinase and cytosine deaminase; however, such an effect has not previously been described using NR. We have preliminary data suggesting an immune bystander effect with NR to further examine these effects and their potential enhancement by cytokines, an adenoviral vector containing CMV-NR, an internal ribosome entry site (IRES) and the gene for murine GM-CSF (mGM-CSF) was constructed. The NR-GM-CSF virus was validated in 2 experimental models and demonstrated increased therapeutic efficacy in the MC26 murine colorectal tumour model. These data illustrate that the combination of suicide gene therapy using NR and CB1954 with immune stimulation via GM-CSF gives an improved response compared to either modality alone and suggests that the immune component of this response may be beneficial in combating unresectable, metastatic disease and preventing tumour recurrence.

Adenocarcinoma↗
PubMed2003

Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial.

BACKGROUND: The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver. METHODS: We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat. FINDINGS: 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival. INTERPRETATION: Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Adenocarcinoma↗
PubMed2003

Colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of mortality and accounts for approximately 200000 deaths per year in Europe and the USA. Chemotherapy and radiotherapy have established roles in the treatment of colorectal cancer and can contribute to cure rate, prolongation of survival, reduction of local rates of recurrence and enhanced quality of life in patients with advanced disease. However, over the past few years there have been major advances in our understanding of the molecular basis of this tumour and its progression from adenoma to carcinoma that hold potential for translation into novel strategies for the treatment of CRC. Furthermore, newer agents directed against different intracellular targets have also been shown to be efficacious in CRC treatment. Such improvements should continue to lead to increased cure rates in early disease and better overall survival in advanced cases. The aim of this review is to provide an overview of the pathogenesis of CRC and to present the evidence base for chemotherapy and some of the novel strategies that are currently being evaluated in phase I and II trials.

Antineoplastic Agents↗
PubMed2003

Use of a phage display library to identify oligopeptides binding to the lumenal surface of polarized endothelium by ex vivo perfusion of human umbilical veins.

Human endothelial-specific targeting peptides were identified by biopanning within freshly-obtained human umbilical cords. Umbilical veins were cleaned in situ and M13 phage display libraries were passed through the cords. Tightly bound phage were recovered following isolation of endothelial cells by collagenase digestion and homogenisation, allowing production of enriched phage libraries for subsequent rounds of panning. After five rounds of biopanning, five promising sequences were selected and the binding of the corresponding phage clones was compared in perfused umbilical veins. Each of these peptides showed substantial binding, although the clone encoding the heptapeptide KPSGLTY showed the greatest, some 89-times greater than insertless phage. Binding of this phage clone was examined to cells in vitro, where it demonstrated at least five-times greater binding to isolated human umbilical vein endothelial cells than to 911, SKOV3, B16F10 and Cos7 cells. These initial peptides may prove useful targeting agents for endothelial-selective delivery, and this powerful approach should be readily applicable to biopanning in a broad range of human vessels ex vivo.

Animals↗
PubMed2003

Immunotherapy for colorectal cancer.

There have been significant improvements in the diagnosis and treatment of colorectal cancer over the past 15 years. However, some 30% of patients with colorectal cancer have disseminated disease at presentation, and furthermore, 50% of patients initially believed to be cured by surgery subsequently relapse and die of the disease. Novel treatment concepts based on understanding the molecular signatures that separate tumor from normal epithelium, such as immunotherapy, are aimed at abolishing microscopic residual disease post standard treatment. The authors provide an overview of progress in the development of specific and nonspecific immunotherapies and explain why definition of end-points and early translation of immunotherapy into the adjuvant field are key to effective use of such agents in the clinical setting.

Animals↗
PubMed2003

CB 1954: from the Walker tumor to NQO2 and VDEPT.

CB 1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide] has been the subject of continued interest for over 30 years. As an anti-cancer agent, it represents one of the very few examples of a compound that shows real anti-tumor selectivity. Unfortunately, for the treatment of human disease, this anti-tumor selectivity was seen only in certain rat tumors. The basis for the anti-tumor selectivity of CB 1954 is that it is a prodrug that is enzymatically activated to generate a difunctional agent, which can form DNA-DNA interstrand crosslinks. The bioactivation of CB 1954 in rat cells involves the aerobic reduction of its 4-nitro group to a 4-hydroxylamine by the enzyme NQO1 (DT-diaphorase). The human form of NQO1 metabolizes CB 1954 much less efficiently than rat NQO1. Thus human tumors are insensitive to CB 1954. In view of the proven success of CB 1954 in the rat system, it would be highly desirable to re-create its anti-tumor activity in man. This has led to the development of CB 1954 analogs and other prodrugs activated by nitroreduction such, as those based on a self-immolative activation mechanism. A gene therapy-based approach for targeting cancer cells and making them sensitive to CB 1954 and related compounds has been developed. VDEPT (gene-directed enzyme prodrug therapy) has been used to express an E. coli nitroreductase in tumor cells and human tumor cells transduced to express this enzyme are very sensitive to prodrugs activated by nitroreduction. CB 1954 is in clinical trial for this application. Recently it has been shown that a latent nitroreductase is present in some human tumors. This is NQO2--an enzyme that requires for activity, the non-biogenic compound dihydronicotinamide riboside (NRH) as a cosubstrate. When active, NQO2 is 3000 times more effective than human DT-diaphorase in the reduction of CB 1954. NRH and reduced pyridinium derivatives that, like NRH, act as co-substrates for NQO2, produce a dramatic increase in the cytotoxicity of CB 1954 against human cell lines in vitro and its anti-tumor activity against certain human xenografts in vivo. NQO2 activity is substantially raised in tumor samples from colorectal and hepatoma patients (up to 14-fold). A phase I clinical trial of an NQO2 co-substrate with CB 1954 is scheduled.

Animals↗
PubMed2002

Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway.

Metalloproteinases (MMP) produced by both cancer and normal stromal fibroblast cells play a critical role in the metastatic spread of tumours, however little is known of the regulation of their release. In this report we demonstrate that breast cancer cells in culture release apparently full length soluble EMMPRIN that promotes the release of pro-MMP2 from fibroblasts. The generation of MMP2 is mediated by activation of phospholipase A(2) and 5-lipoxygenase. These results suggest that the production of soluble EMMPRIN, phospholipase A(2) and 5-lipoxygenase activities are sites for potential therapeutic intervention.

Antigens, CD↗
PubMed2002

Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin.

PURPOSE: Preclinical studies have shown good anticancer activity following targeting of a polymer bearing doxorubicin with galactosamine (PK2) to the liver. The present phase I study was devised to determine the toxicity, pharmacokinetic profile, and targeting capability of PK2. PATIENTS AND METHODS: Doxorubicin was linked via a lysosomally degradable tetrapeptide sequence to N-(2-hydroxypropyl)methacrylamide copolymers bearing galactosamine. Targeting, toxicity, and efficacy were evaluated in 31 patients with primary (n = 25) or metastatic (n = 6) liver cancer. Body distribution of the radiolabelled polymer conjugate was assessed using gamma-camera imaging and single-photon emission computed tomography. RESULTS: The polymer was administered by intravenous (i.v.) infusion over 1 hour, repeated every 3 weeks. Dose escalation proceeded from 20 to 160 mg/m(2) (doxorubicin equivalents), the maximum-tolerated dose, which was associated with severe fatigue, grade 4 neutropenia, and grade 3 mucositis. Twenty-four hours after administration, 16.9% +/- 3.9% of the administered dose of doxorubicin targeted to the liver and 3.3% +/- 5.6% of dose was delivered to tumor. Doxorubicin-polymer conjugate without galactosamine showed no targeting. Three hepatoma patients showed partial responses, with one in continuing partial remission 47 months after therapy. CONCLUSION: The recommended PK2 dose is 120 mg/m(2), administered every 3 weeks by IV infusion. Liver-specific doxorubicin delivery is achievable using galactosamine-modified polymers, and targeting is also seen in primary hepatocellular tumors.

Antineoplastic Agents↗
PubMed2002

Ras as a target in cancer therapy.

Ras proteins are guanine nucleotide-binding proteins that are central to the control of normal and transformed cell growth and that are mutated in approximately 30% of human cancers. Binding of ligands to various growth factor receptors activates Ras and subsequently a plethora of downstream effectors including the Raf-1/mitogen-activated protein kinase pathway. For effective ras functioning and for transformation, Ras proteins must undergo post-translational modifications that facilitate their attachment to the plasma membrane. Farnesylation, catalysed by farnesyl protein transferase (FPT), is the first and the most important of these modifications; inhibition of which ablates ras activity, resulting in significant anti-proliferative effect in vitro and in human cancer xenograft models. FPT inhibitors are being assessed in a range of phase I and phase II trials, which incorporate both pharmacokinetic and dynamic end-points. In addition, ras mutations can also generate neo-epitopes for cytotoxic and helper T-cell recognition, rendering ras-mutated tumours a potential target for immunotherapy. Though their clinical evaluation is still in infancy, these two modes of ras targeting represent rational therapeutic strategies that can undergo mechanistic evaluation in the clinic.

Alkyl and Aryl Transferases↗
PubMed2002

Identification of FGF receptor-binding peptides for cancer gene therapy.

Linear FGF receptor-binding heptapeptides were identified by phage display using sequential rounds of biopanning against cells with displacement of phage by FGF2. The consensus motif MXXP was iterated after four to five rounds and the peptide MQLPLAT was studied in depth. Phage bearing MQLPLAT showed high levels of binding to FGF receptor positive cells, with over 90% of phage bound being eluted competitively by adding free FGF2. MQLPLAT phage showed only limited binding to Cos7 cells deficient in receptors for FGF. MQLPLAT phage bound to SKOV3 cells with a K(d) of 2.51 x 10(-10) M. Although binding could be blocked by preincubation with free FGF2, heparin could not displace the phage. Use of MQLPLAT to target polyelectrolyte gene delivery vectors in vitro in the presence of serum achieved up to 40-fold greater transgene transduction than nontargeted vectors. MQLPLAT phage were administered into gastric carcinomas via the tumor-feeding artery immediately following resection from patients. The phage showed up to 9-fold more accumulation in the tumor than in adjacent regions of normal tissue, whereas control phage showed less than 2-fold. These peptides should provide useful ligands for specific delivery of gene therapy vectors to clinically relevant targets.

Amino Acid Motifs↗
PubMed2002

Gene therapy for colorectal cancer.

Gene therapy has been developed as a potential novel treatment modality for colorectal cancer. The preclinical data have been promising and several clinical trials are under way for colorectal cancer. Data from many phase 1 trials have proven the safety of the reagents, but have not yet demonstrated significant therapeutic benefit. In order to refine this approach, continuing efforts should be made to improve the antitumour potency, efficiency of gene delivery, and accuracy of gene targeting. It is likely that gene therapy will be integrated into pre-existing therapies including surgery, chemotherapy and radiotherapy to establish its niche in tomorrow's medicine.

Clinical Trials, Phase I as Topic↗
PubMed2002

Capecitabine/irinotecan combination regimens in colorectal cancer.

Capecitabine (Xeloda) and irinotecan (CPT-11, Camptosar) both have demonstrated single-agent activity in patients with colorectal cancer. In an analysis of pooled results of two phase III studies, capecitabine provided advantages over intravenous fluorouracil (5-FU) plus leucovorin in patients with metastatic colorectal cancer. In another analysis, metastatic colorectal cancer patients who received irinotecan along with 5-FU plus leucovorin had significantly improved overall survival as compared with those who received 5-FU plus leucovorin alone. Capecitabine and irinotecan have distinct mechanisms of action and only partially overlapping toxicities. Combinations of these agents therefore are being explored in patients with colorectal cancer. This report briefly reviews current and ongoing trials evaluating capecitabine/irinotecan combination regimens in treating this disease.

Antineoplastic Combined Chemotherapy Protocols↗