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At least 577 records · Page 32Linked to original sources
PubMed2002

Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery?

Systemic administration of currently manufactured viral stocks has not so far achieved sufficient circulating titers to allow therapeutic targeting of metastatic disease. This is due to low initial viral titers, immune inactivation, nonspecific adhesion, and loss of particles. One way to exploit the elegant molecular manipulations that have been made to increase vector targeting is to protect these vectors until they reach the local sites of tumor growth. Various cell types home preferentially to tumors and can be loaded with the constructs required to produce targeted vectors. Here we discuss the potential of using such cell carriers to chaperone precious vectors directly to the tumors. The vectors can incorporate mechanisms to achieve tumor site-inducible expression, along with tumor cell-specific expression of the therapeutic gene and/or replicating viral genomes that would be released at the tumor. In this way, the great advances that have so far been made with the engineering of vector tropisms might be genuinely exploited and converted into clinical benefit.

Cell Transplantation↗
PubMed1999

Toward an enzyme/prodrug strategy for cancer gene therapy: endogenous activation of carboxypeptidase A mutants by the PACE/Furin family of propeptidases.

In an effort to develop a gene-dependent enzyme/prodrug therapy (GDEPT) for tumor-specific delivery of methotrexate (MTX) we have chosen to construct mutant forms of carboxypeptidase A1 (CPA) that circumvent the requirement for trypsin-dependent activation. The basis of this strategy is that methotrexate-alpha-peptides are inefficient substrates for the reduced folate carrier (RFC) and hence cannot be internalized by cells. However, the blocking amino acid can be cleaved by CPA to liberate MTX, which is then internalized by the RFC, resulting in inhibition of dihydrofolate reductase and cytotoxicity. A battery of mutant CPAs was generated, in which the putative trypsin cleavage sites in the propeptide were mutated to the consensus recognition sequence for mammalian subtilisin-like propeptidases. These mutant forms of CPA were evaluated for expression, activation, and catalytic activity by transiently transfecting them into COS-1 cells both in the absence and in the presence of cotransfected propeptidases. CPA95 was identified as the most efficiently cleaved mutant, and further studies of this mutant indicated that the endogenously activated enzyme had kinetic parameters identical to those of the trypsin-activated wild-type protein. In addition, endogenously activated CPA95 could effectively sensitize cells to MTX-Phe in culture, decreasing the IC50 of MTX-Phe from 25- to 250-fold in squamous cell carcinoma cells expressing active CPA as compared with the parental lines.

Animals↗
PubMed1995

Cancer gene therapy using plasmid DNA: pharmacokinetic study of DNA following injection in mice.

The fate of plasmid DNA complexed with cationic lipids delivered intravenously in mice was evaluated at selected timepoints up to 6 months postinjection. Blood half-life and tissue distribution of plasmid DNA and potential expression in tissues were examined. Southern blot analyses of blood indicated that intact plasmid DNA was rapidly degraded, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. Southern analyses of tissue demonstrated that intact DNA was differentially retained in the lung, spleen, liver, heart, kidney, marrow, and muscle up to 24 hr postinjection. After 7 days, no intact plasmid DNA was detectable by Southern blot analysis; however, the plasmid was detectable by the polymerase chain reaction (PCR) in all tissues examined at 7 and 28 days postinjection. At 6 months postinjection, femtogram levels of plasmid were detected only in muscle. Immunohistochemical analyses did not detect encoded protein in the tissues harboring residual plasmid at 1 or 7 days postinjection.

Animals↗
PubMed1997

Bystander effects of different enzyme-prodrug systems for cancer gene therapy depend on different pathways for intercellular transfer of toxic metabolites, a factor that will govern clinical choice of appropriate regimes.

Transfer of suicide genes into tumor cells renders them sensitive to cytotoxic effects of specific prodrugs. We show here that both the herpes simplex virus thymidine kinase/ganciclovir (tk/GCV) and thymidine phophorylase/5'-deoxy-5-fluorouridine (tp/DFUR) suicide gene systems can induce cell death in tumor cells. Additionally in mixed cultures of cells with and without the suicide gene, death occurred in both cell types, indicative of a bystander effect. We demonstrate, in human and rodent cell lines, that the tk/GCV bystander effect requires gap junctional intercellular communication (GJIC). Where cultures lack GJIC, no bystander effect was observed. In communicating cultures, no correlation between level of GJIC and bystander effect was seen and this was due to high levels of tk activity. Additionally, we demonstrate that transfer of toxic metabolites from tk+ to tk- cells occurs within 2 hr of GCV application and, as no apoptosis could be detected until after this time, apoptosis is the result, not the cause, of the tk/GCV bystander effect. In the tp/DFUR system, a medium-mediated bystander effect, independent of GJIC and apoptosis, was observed. We demonstrated that combining tk/GCV and tp/DFUR suicide gene systems in culture was more effective than either therapy alone.

Animals↗