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Biomedical subjects

Theodore S Lawrence

Publications and source records attributed to Theodore S Lawrence.

At least 55 records · Page 3Linked to original sources
PubMed2004

3H dendrimer nanoparticle organ/tumor distribution.

PURPOSE: To determine the in vivo biodistribution for differently charged poly(amidoamine) (PAMAM) dendrimers in B16 melanoma and DU145 human prostate cancer mouse tumor model systems. METHODS: Neutral (NSD) and positive surface charged (PSD) generation 5 (d = 5 nm) PAMAM dendrimers were synthesized by using 3H-labeled acetic anhydride and tested in vivo. Dendrimer derivatives were injected intravenously, and their biodistribution was determined via liquid scintillation counting of tritium in tissue and excretory samples. Mice were also monitored for acute toxicity. RESULTS: Both PSD and NSD localized to major organs and tumor. Dendrimers cleared rapidly from blood, with deposition peaking at 1 h for most organs and stabilizing from 24 h to 7 days postinjection. Maximal excretion occurred via urine within 24 h postinjection. Neither dendrimer showed acute toxicity. CONCLUSIONS: Changes in the net surface charge of polycationic PAMAMs modify their biodistribution. PSD deposition into tissues is higher than NSD, although the biodistribution trend is similar. Highest levels were found in lungs, liver, and kidney, followed by those in tumor, heart, pancreas, and spleen, while lowest levels were found in brain. These nanoparticles could have future utility as systemic biomedical delivery devices.

Animals↗
PubMed2004

Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector.

One strategy for improving selectivity of gene therapy is the use of a replication-activated adenovirus vector that mediates transgene expression specifically in tumor cells through homologous recombination of viral genomes. In this study, we compared replication-activated adenovirus containing inverted repeats (Ad.IR-BG) with IR-deficient virus (Ad.BG) for selective gene expression in hepatocellular carcinoma and colon carcinoma metastases in the liver. We found that Ad.IR-BG conferred specific gene expression in both carcinoma cells, with minimal expression in hepatocytes and colon epithelial cells. This occurred through viral DNA recombination in Ad.IR-BG-infected tumor cells but not in normal cells. Hydroxyurea, which blocks DNA replication, inhibited DNA recombination and beta-gal expression in Ad.IR-BG-infected but not Ad.BG-infected tumor cells. Finally, systemic injection of Ad.IR-BG into tumor xenografts in nude mice significantly improved selectivity of gene expression in tumors with minimal expression in normal tissues. Viral DNA recombination, which was absent in normal liver, was detected in Ad.IR-BG-infected tumors but not in Ad.BG-infected tissue. These findings demonstrated that replication-activated adenovirus can mediate tumor-specific gene expression through viral DNA recombination, which is otherwise deficient in normal cells.

Adenoviridae↗
PubMed2003

Alterations in normal liver doses due to organ motion.

PURPOSE: To assess the clinical significance of differences between treatment planning calculations based on static computed tomography (CT) and more realistic predictions of the actual delivered dose to intrahepatic lesions by a geometric convolution approach that accounts for random setup variations and breathing-induced organ motion. MATERIALS AND METHODS: We recalculated target and normal liver doses for 40 patients previously treated on a conformal therapy dose escalation protocol to include the effect of setup uncertainties and liver motion due to patient breathing. Initial three-dimensional (3D) dose calculations based on pretreatment CT scans taken with voluntary breath-hold at normal exhalation were convolved with 3D anisotropic probability distribution functions reflecting population measurements of position setup variation. The convolution also included a distribution function (one-dimensional, inferior-superior direction only) representing the asymmetric temporal pattern (biased toward exhalation, based on population measurements) of a typical breathing cycle, scaled in amplitude for each patient. RESULTS: After convolution, the minimum clinical target volume (CTV) dose met or exceeded the minimum planning target volume (PTV) dose from the static plan in all but one case, indicating adequate PTV design. However, clinically relevant and statistically significant increases (decreases) in liver normal tissue complication probability (NTCP) from values computed for the static cases occurred for tumors located toward the bottom (top) of the liver, as predicted for these patients scanned at exhalation. The change in liver NTCP (from a nominal 20%) ranged from +12.0% to -11.7% (average magnitude change 3.9% [sigma = 3.3%]). Changes in prescription dose required to restore the original 20% NTCP ranged from -3.7 Gy to +7.9 Gy (average magnitude change 1.9 Gy [sigma = 1.9 Gy]). CONCLUSIONS: Although the PTV concept can ensure adequate CTV coverage, the doses to normal liver are incorrectly modeled without including patient-related geometric uncertainties.

Algorithms↗
PubMed2003

Regional delivery and selective expression of a high-activity yeast cytosine deaminase in an intrahepatic colon cancer model.

A major potential limitation to the success of enzyme prodrug gene therapy is the toxicity that could result from gene expression in normal tissues. In this study, we investigated the use of an enhanced human carcinoembryonic antigen (CEA) promoter for yeast cytosine deaminase (yCD), which converts 5-fluorocytosine to 5-fluorouracil, to increase targeting while maintaining activity both in cell culture and in nude rats bearing intrahepatic xenografts. We found that an enhanced CEA-yCD adenoviral vector can achieve significantly greater yCD expression in CEA-expressing colon carcinoma cell lines (LoVo, HT29, and CaCo2) compared with a nonspecific Rous sarcoma virus-yCD virus. In contrast, infection with CEA-yCD led to lower or equivalent yCD expression in normal hepatocytes or fibroblasts compared with that produced by the RSV-yCD. Adenovirus administered in the portal vein or the hepatic artery of nude rats bearing intrahepatic LoVo colon carcinomas could mediate beta-galactosidase expression equally in liver and tumors under the control of cytomegalovirus, a nonspecific promoter. However, infusion of CEA-yCD virus markedly increased yCD expression in tumors over normal liver (>4-fold) measured both by levels of mRNA and yCD activity. Moreover, the efficiency of 5-fluorocytosine conversion into 5-fluorouracil in tumors was significantly higher than that in normal liver ( approximately 3-fold) in rats receiving portal venous viral infusion of CEA-yCD and subsequent 5FC treatment. Thus, an enhanced CEA promoter can preferentially stimulate yCD gene expression in CEA-expressing cells in vivo. Such tumor-specific expression should prove useful in colorectal cancer gene therapy to achieve selective prodrug conversion in tumors.

Adenoviridae↗
PubMed2003

Conformal chemoradiation for primary and metastatic liver malignancies.

Historically, radiation therapy has played a minor role in the management of patients with unresectable primary hepatobiliary malignancies and liver metastases from colorectal cancer. This can be attributed chiefly to the low tolerance of the whole liver to radiation. Three-dimensional radiation planning techniques have allowed much higher doses of radiation to be delivered to focal liver tumors, while sparing the majority of the normal liver. When combined with fluorodeoxyuridine (FUdR), high-dose focal liver radiation is associated with excellent response rates, local control, and survival in patients with large unresectable tumors. There appears to be a radiation dose response for intrahepatic malignancies. Advancements in tumor imaging, radiation techniques that can safely deliver higher doses of radiation, novel tumor radiation sensitizers, and normal-tissue radioprotectors should substantially improve the outcome of patients with unresectable intrahepatic malignancies treated with chemoradiation.

Combined Modality Therapy↗
PubMed2003

Ionizing radiation increases adenovirus uptake and improves transgene expression in intrahepatic colon cancer xenografts.

Specific targeting and transgene expression in tumors are critical in adenovirus gene therapy for intrahepatic colon carcinoma metastases. In this study, we investigated if ionizing radiation could increase adenoviral uptake by cells. Various human cell lines and rat hepatocytes were irradiated prior to exposure to a cytomegalovirus (CMV) promoter-driven green fluorescent protein (GFP) marker gene adenoviral vector. We found that gamma-radiation increased the number of GFP-positive cells in a dose- and time-dependent manner for most cells, ranging from 4.6- to 27.1-fold after a 4-Gy treatment. No induction occurred for lentiviral vector, lipofection, or naked plasmid exposure. Preincubation of cells with adenovirus failed to show an increase, suggesting that radiation might mediate adenoviral infection by inducing viral uptake into cells. We demonstrated that radiation induced internalization of a fluorescence-labeled adenovirus (Cy3-Ad) and an increase in intracellular viral DNA content. Rats bearing intrahepatic colon carcinoma xenografts were irradiated in the tumor region followed by portal venous administration of an adenoviral vector containing a CMV-beta-galactosidase (beta-gal) gene. Radiation increased beta-gal activity in tumors as much as 5.4-fold after a 25-Gy treatment. These data suggest that a combination of regional radiation treatment with adenovirus gene therapy is a rational strategy for improving adenoviral targeting and transgene expression in tumors.

Adenoviridae↗
PubMed2003

The mechanism of action of radiosensitization of conventional chemotherapeutic agents.

It is not an exaggeration to state that most of the advances in curing cancer in the last decade have come from successful combinations of conventional chemotherapeutic agents with radiation therapy. Further improvements in therapy will depend on understanding the mechanisms by which chemotherapy improves the effectiveness of radiation in model systems and in patients. In this review, we discuss the mechanisms of action of the fluoropyrimidines, gemcitabine, and the platinums. The fluoropyrimidines (5-fluorouracil and fluorodeoxyuridine) increase the effectiveness of radiation chiefly when given before and during radiation. Increased radiation sensitivity occurs in cells that progress inappropriately into S phase in the presence of drug, suggesting a key role for dysregulation of S-phase checkpoints. Gemcitabine may radiosensitize by a similar mechanism, although the relative roles of specific DNA repair pathways (such as homologous end rejoining) and of apoptosis remain to be determined. For both of these categories of drugs, sensitization probably results when cells that are progressing inappropriately through S phase misrepair DNA damage inflicted by radiation. Thus, loss of the S-phase checkpoint in cancer cells may provide the molecular basis for selective killing of tumors compared with normal tissues. Cisplatin has multiple effects on cells, such as adduct formation and DNA damage repair inhibition, but the mechanism for selectivity against cancer cells compared with normal cells is not yet determined. The identification of the enzymatic targets for these drugs offers the potential to develop predictive assays for response and to develop methods of imaging the progress of therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced expression.

In an effort to search for genes responsible for cell growth arrest and/or apoptosis associated with p53 signaling pathways, we profiled a human lung carcinoma line H1299, expressing a temperature-sensitive p53 (V138) against Affymetric human U95Av2 GeneChip A, consisting of 12 000 genes. 133 genes were identified that were either induced or repressed in response to p53-dependent cell growth arrest and apoptotic conditions. Among them, the beta1 subunit, but not other subunits of the AMP-activated protein kinase (AMPK) was strongly induced. The p53 consensus binding site search in the AMPK-beta1 promoter and the first intron identified four such putative sites. However, p53 failed to bind to any of these sites as assayed by in vitro gel retardation and in vivo chromatin immunoprecipitation. Furthermore, northern analysis showed that induction of this gene is independent of p53, as increased expression of the gene was observed in p53 null H1299/Neo control cells when the temperature was shifted to 32 degrees C. Moreover, a DNA damaging agent, etoposide, also induced beta1 subunit expression in multiple human tumor cells, regardless of p53 status. Thus, the beta1 subunit of AMPK is not a p53 downstream target gene, but can be induced by cold shock or the chemotherapeutic drug, etoposide in a p53-independent manner. To determine the biological significance of AMPK-beta1 induction, we over-expressed the gene in two tumor cell lines, H1299 and U2-OS. In both lines, forced AMPK-beta1 expression inhibits tumor cell growth, suggesting that AMPK-beta1 induction may facilitate stress-induced growth inhibition and cell killing.

AMP-Activated Protein Kinases↗
PubMed2003

Evaluation of cancer therapy using diffusion magnetic resonance imaging.

Assessment of the effectiveness of cancer therapy traditionally relies on comparison of tumor images acquired before and after therapeutic intervention by inspection of gross anatomical images to evaluate changes in tumor size. The potential for imaging to provide additional insights related to the therapeutic impact would be enhanced if a specific parameter or combination of parameters could be identified that reflect tissue changes at the cellular or physiological level. This information could also provide a more sensitive and earlier indicator of treatment response in an individual animal or patient. Diffusion magnetic resonance imaging can detect relatively small changes in tissue structure at the cellular level and thus provides an opportunity to quantitatively and serially follow therapeutic-induced changes in solid tumors. This article provides an overview of the use of diffusion magnetic resonance imaging as a surrogate marker for quantitating treatment responsiveness in both preclinical and clinical studies.

Animals↗
PubMed2003

Radiation sensitizers and targeted therapies.

Chemotherapeutic agents that are highly responsive to ionizing radiation and enhance the effectiveness of radiation treatment are termed radiation sensitizers. Radiation sensitizers act in a number of ways to make cancer cells more susceptible to death by radiation than surrounding normal cells, and several such compounds are now available for the treatment of solid tumors. This review discusses the biology that underlies chemotherapy and radiation interactions for one radiosensitizer--gemcitabine (Gemzar). It also provides a brief assessment of how to modify treatment regimens for various cancers to maximize the radiosensitization potential of gemcitabine in order to further increase efficacy. Newer molecularly targeted agents and their antitumor potential as monotherapy or in combination with radiation are also reviewed.

Deoxycytidine↗
PubMed2002

On the development of gemcitabine-based chemoradiotherapy regimens in pancreatic cancer.

The use of chemotherapy with concurrent radiation therapy remains a standard treatment option for patients with unresectable or resected adenocarcinoma of the pancreas. This treatment strategy is based in large part on data from serial Gastrointestinal Tumor Study Group trials that have included 5-fluorouracil. Unfortunately, the majority of patients continue to succumb to the disease process. Recently, there has been a resurgence in clinical trials utilizing gemcitabine as a single agent, in combination chemotherapy regimens, and with concurrent radiation therapy. Use with concurrent radiation therapy is based in part on laboratory studies investigating mechanisms of radiosensitization and strategies that might increase the therapeutic index. In the current review, the authors summarize the preclinical data that support the use of gemcitabine as a radiosensitizing agent and the clinical trials that have been conducted to date. Issues regarding the use of gemcitabine in concurrent radiotherapy regimens need to be viewed in the context of both local and distant disease control, given the radiosensitizing and systemic activity of this agent.

Antimetabolites, Antineoplastic↗
PubMed2002

Analysis of radiation-induced liver disease using the Lyman NTCP model.

PURPOSE: To describe the dose-volume tolerance for radiation-induced liver disease (RILD) using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model. METHODS AND MATERIALS: A total of 203 patients treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose-volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD < o r =4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD. RESULTS: Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The "n" parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was <31 Gy. Multivariate analysis demonstrated that in addition to NTCP and the mean liver dose, a primary hepatobiliary cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender were associated with RILD. For 169 patients treated with fluorodeoxyuridine, the refined LKB model parameters were n = 0.97, m = 0.12, tolerance dose for 50% complication risk for whole organ irradiated uniformly [TD50(1)] = 45.8 Gy for patients with liver metastases, and TD50(1) = 39.8 Gy for patients with primary hepatobiliary cancer. CONCLUSION: These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose-volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.

Adult↗
PubMed2002

Concurrent chemoradiotherapy with gemcitabine and cisplatin for pancreatic cancer: from the laboratory to the clinic.

PURPOSE: We have reported that gemcitabine and concurrent radiation is a promising therapy for patients with pancreatic cancer. We investigated whether the addition of cisplatin, which may increase the systemic efficacy of gemcitabine, would be synergistic with gemcitabine and/or radiation in human pancreatic cancer cell lines. METHODS AND MATERIALS: BxPc3 and Panc-1 human pancreatic cancer cells were treated with three different schedules before radiation: (A) a sequential incubation of gemcitabine for 2 h followed by cisplatin for 2 h, (B) gemcitabine for 2 h, followed by washout of drug, replenishment of media for a 24-h incubation, followed by cisplatin for 2 h, and (C) gemcitabine for 24 h with a concurrent incubation of cisplatin for the last 2 h. Cells were assessed for clonogenic survival using a standard assay. Synergism was evaluated by the median effect analysis. RESULTS: The schedule shown to be maximally synergistic for both cell lines was the consecutive 2-h gemcitabine, 2-h cisplatin exposure, particularly at surviving fractions of <0.5. Cisplatin did not produce radiosensitization nor did it affect gemcitabine-mediated radiosensitization. CONCLUSION: Cisplatin produces synergistic cytotoxicity with gemcitabine without compromising gemcitabine-mediated radiosensitization. On the basis of these laboratory and previous clinical observations, we have initiated a Phase I trial of cisplatin plus gemcitabine and radiotherapy in patients with unresectable pancreatic cancer.

Cisplatin↗
PubMed2002

High and selective expression of yeast cytosine deaminase under a carcinoembryonic antigen promoter-enhancer.

Yeast cytosine deaminase (yCD)-based gene therapy offers the potential for selective production of the cytotoxic and radiosensitizing drug 5-fluorouracil (5-FU) from the benign prodrug 5-fluorocytosine within colorectal cancers. Although previous attempts to target therapy to colorectal cancer using the carcinoembryonic antigen (CEA) promoter have demonstrated specificity, this has been achieved at the cost of 10- to 300-fold loss in activity compared with strong but nonspecific rous sarcoma virus (RSV) or cytomegalovirus promoters. We developed a highly specific and active gene transfer method for colorectal cancer using CEA under control of a promoter-enhancer. We compared the RSV promoter-derived with the CEA promoter-enhancer-derived transgene expression in 10 different cell lines with differing CEA status. We found that the transgene expression resulting from both transient transfection and adenoviral infection with the CEA promoter-enhancer was as strong as the RSV promoter while maintaining specificity for CEA-producing cell lines. For instance, when we compared yCD expression between LoVo (CEA+) and human fibroblast (CEA-), we found a 30-fold-increased yCD expression in LoVo cells from CEA-enhancer adenovirus although there was no difference in the yCD expression between the cell lines when infected with RSV/yCD virus. This specificity was also achieved while maintaining a higher yCD enzyme activity than we obtained with RSV/yCD adenovirus in an HT-29 intrahepatic tumor model. We then compared the response of HT-29 xenografts to treatment with 5-fluorocytosine and yCD adenovirus driven by either the RSV or the CEA promoter-enhancer and found similar tumor growth inhibition. These findings suggest that the CEA promoter-enhancer strategy confers specificity while preserving activity and is worth exploring in additional animal and, potentially, clinical trials.

Adenoviridae↗
PubMed2002

Daily targeting of intrahepatic tumors for radiotherapy.

INTRODUCTION: A system has been developed for daily targeting of intrahepatic tumors using a combination of ventilatory immobilization, in-room diagnostic imaging, and on-line setup adjustment. By reducing geometric position uncertainty, as well as organ movement, this system permits reduction of margins and thus potentially higher treatment doses. This paper reports our initial experience treating 8 patients with focal liver tumors using this system. METHODS AND MATERIALS: The system includes diagnostic X-ray tubes mounted on the wall and ceiling of a treatment room, an active matrix flat panel imager, in-room control for image acquisition and setup adjustment, and a ventilatory immobilization system via active breathing control (ABC). Eight patients participated in the study, two using an early prototype ABC unit, and the remaining six with a commercial ABC system and improved setup measurement tools. Treatment margins were reduced, and dose consequently increased because of increased confidence in target position under this protocol. After daily setup via skin marks, orthogonal radiographs were acquired at suspended ventilation. The images were aligned to the CT model using the diaphragm for inferior-superior (IS) alignment, and the skeleton for left-right (LR) and anterior-posterior (AP) alignment. Adjustments were made for positioning errors greater than a threshold (3 or 5 mm). After treatment, retrospective analysis determined the final setup accuracy, as well as the error in initial setup measurement performed before setup adjustment. RESULTS: Two hundred sixty-two treatment fractions were delivered on eight patients, with 171 treatments requiring repositioning. Typical treatment times were 25-30 min. Patients were able to tolerate ABC throughout the course of treatment. Breath holds up to 35 s long were used for treatment. The use of on-line imaging and setup adjustment reduced setup errors (sigma) from 4.0 mm (LR), 6.7 mm (IS), and 3.8 mm (AP) to 2.1 mm (LR), 3.5 mm (IS), and 2.3 mm (AP). Prescribed doses were increased using this system by an average of 5 Gy. CONCLUSIONS: Daily targeting of intrahepatic targets has been demonstrated to be feasible. The potential for reduction in treatment margin and consequential safe dose escalation has been demonstrated, while maintaining reasonable treatment delivery times.

Dose Fractionation, Radiation↗
PubMed2002

Small-molecule tyrosine kinase inhibitors as radiosensitizers.

The discovery of a class of highly selective and potent compounds called the 4-anilinoquinazolines has led to the development of small-molecule tyrosine kinase inhibitors as potential anticancer agents. These agents inhibit essential cellular pathways in growth factor expression and can be administered as an oral formulation. Some of these agents, such as ZD1839 and OSI-774, tend to bind in vitro only to the epidermal growth factor receptor tyrosine kinase while others, such as CI-1033, bind to multiple members of the ErbB family. The first clinical compounds that were developed, such as ZD1839, were reversible inhibitors. More recently, irreversible compounds have been developed that may be more effective at producing long-term suppression. Very little published work is available concerning the interaction of small-molecule tyrosine kinase inhibitors with radiation. This article presents our data on the interactions of CI-1033 with radiation.

Enzyme Inhibitors↗