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Biomedical subjects

David J Kerr

Publications and source records attributed to David J Kerr.

26 records · Page 2Linked to original sources
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↗
PubMed2002

Clinical experience with adenovirus in cancer therapy.

Gene therapy is emerging as a novel treatment for cancer. Preclinical data utilizing adenovirus vectors have been promising and several clinical trials employing this employing this vector are underway. Data from many phase I trials have established the safety of adenovirus vectors, but have not as yet demonstrated significant therapeutic benefit. In order to refine this approach, continuing efforts are being made to improve antitumor potency, efficiency of gene delivery and accuracy of vector targeting. It is anticipated that adenovirus-mediated gene therapy will be integrated with existing treatment modalities, including surgery, chemotherapy and radiotherapy, to facilitate improvement in cancer treatments in the future.

Adenoviridae↗
PubMedDate not supplied

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Antineoplastic Agents↗