PubMed Health⌕ Search

Biomedical subjects

Theodore S Lawrence

Publications and source records attributed to Theodore S Lawrence.

At least 37 records · Page 2Linked to original sources
PubMed2005

Evaluation of the functional diffusion map as an early biomarker of time-to-progression and overall survival in high-grade glioma.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water (V(T)) was different between patients with progressive disease (PD) vs. stable disease (SD) (P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Adult↗
PubMed2005

Identification of peptides that bind to irradiated pancreatic tumor cells.

PURPOSE: Peptides targeting tumor vascular cells or tumor cells themselves have the potential to be used as vectors for delivering either DNA in gene therapy or antitumor agents in chemotherapy. We wished to determine if peptides identified by phage display could be used to target irradiated pancreatic cancer cells. METHODS AND MATERIALS: Irradiated Capan-2 cells were incubated with 5 x 10(12) plaque-forming units of a phage display library. Internalized phage were recovered and absorbed against unirradiated cells. After five such cycles of enrichment, the recovered phage were subjected to DNA sequencing analysis and synthetic peptides made. The binding of both phage and synthetic peptides was evaluated by fluorescence staining and flow cytometry in vitro and in vivo. RESULTS: We identified one 12-mer peptide (PA1) that binds to irradiated Capan-2 pancreatic adenocarcinoma cells but not to unirradiated cells. The binding of peptide was significant after 48 h incubation with cells. In vivo experiments with Capan-2 xenografts in nude mice demonstrated that these small peptides are able to penetrate tumor tissue after intravenous injections and bind specifically to irradiated tumor cells. CONCLUSION: These data suggest that peptides can be identified that target tumors with radiation-induced cell markers and may be clinically useful.

Animals↗
PubMed2005

Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine.

The deoxycytidine analogue 2',2'-difluoro-2'-deoxycytidine (gemcitabine) is a potent radiation sensitizer in a variety of solid tumors and tumor cell lines. Previous studies have shown that radiosensitization by gemcitabine is accompanied by simultaneous depletion of dATP pools (through ribonucleotide reductase inhibition) and accumulation in the S-phase of the cell cycle. Because of the importance of cell cycle redistribution in gemcitabine-mediated radiosensitization, we investigated the role of checkpoint kinase (Chk) 1 and Chk2 in gemcitabine-induced cell cycle arrest. We hypothesized that gemcitabine might induce Chk1 or Chk2 signal transduction pathways that mediate S-phase arrest. We found that radiosensitizing concentrations of gemcitabine induced accumulation of phosphorylated Chk1 and Chk2 and down-regulation of Cdc25A in BxPC-3 (10 nmol/L), Panc-1 (100 nmol/L), A549 (30 nmol/L), RKO (30 nmol/L), and SW620 (30 nmol/L) cells. Depletion of Chk1 from Panc-1 cells prevented the down-regulation of Cdc25A in response to gemcitabine. Furthermore, Chk1 depletion permitted Panc-1 and SW620 cells treated with gemcitabine to enter mitosis despite incomplete DNA synthesis. However, depletion of neither Chk1 nor Chk2 abrogated the inhibition of DNA synthesis in response to gemcitabine. These results provide evidence that Chk1 negatively regulates entry into mitosis in response to gemcitabine. Furthermore, these data imply that Chk1 acts to coordinate the cell cycle with DNA synthesis, thus preventing premature mitotic entry in gemcitabine-treated cells.

Cell Cycle↗
PubMed2005

Use of principal component analysis to evaluate the partial organ tolerance of normal tissues to radiation.

PURPOSE: To describe a novel method of analyzing partial volume effects of normal tissues to radiation. With this approach, principal component analysis (PCA) is used to efficiently describe the variance in cumulative dose-volume histogram (cDVH) morphology. The independent features of cDVHs that describe the largest variance are then investigated regarding complication risk. METHODS AND MATERIALS: Principal component analysis was used to describe the variance in the morphology of normal tissue cDVHs, irrespective of complication, by summarizing the largest source of variation within the first principal component (PC), the next largest in the second PC, and so on. Plots relating the most meaningful PCs were constructed. Ideally, cDVHs associated with a complication would yield PC values that could be easily segregated from cDVHs without a complication. Two data sets were evaluated with this approach: 90 parotid gland cDVHs (36 with complications) and 203 liver cDVHs (19 with complications). RESULTS: Ninety-four percent and 80% of the variation in cDVH morphology was described with two PCs for the parotid gland and the liver data sets, respectively. Plots of the first and second PC values on a Cartesian plane for both data sets revealed "clusters." For the parotid gland, one cluster contained PCs from parotid gland cDVHs with complications, and the other primarily contained PCs from cDVHs without complications. The first PC value, corresponding to a larger volume treated with 10-60 Gy (2 Gy per fraction), was more likely to be larger in parotid gland cDVHs associated with complications than those without complications. In the plots of PC values of liver cDVHs, whole liver radiation cDVHs were segregated from the other cDVHs. There was a trend for cDVHs with a higher first PC, corresponding to increased volume treated with approximately 10-40 Gy (1.5 Gy b.i.d.), to be associated with increased risk of complication. For partial liver radiation cDVHs there was a trend for cDVHs with a higher first PC, corresponding to an increased volume treated with 5-50 Gy, to be associated with a complication. For each data set, logistic regression modeling revealed that the first PC was significantly associated with a complication developing (p < 0.02). CONCLUSIONS: Principal component analysis can be used to summarize the variance in parallel normal tissue cDVHs, and it can help segregate cDVHs at high or low risk for complications.

Adult↗
PubMed2005

Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer.

PURPOSE: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. METHODS AND MATERIALS: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m2 daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. RESULTS: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. CONCLUSION: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.

Adult↗
PubMed2005

Ionizing radiation-induced adenovirus infection is mediated by Dynamin 2.

Specific viral targeting into intrahepatic tumors remains critical for adenovirus gene therapy in liver cancer. We previously showed that ionizing radiation increases adenovirus uptake and transgene expression in cells and colon cancer xenografts. Here, we tested whether radiation induces viral uptake through virus-cell membrane interaction. We found that radiation (8 Gy) induced adenoviral gene transfer in rat hepatocytes (WB) and human colon carcinoma cells (LoVo). This induction (24.4- and 6.5-fold, respectively) and viral uptake were significantly diminished by preincubation with antibody for Dynamin 2 but not for Coxsackie adenovirus receptor or for integrin alpha(v). Radiation-induced Dynamin 2 expression was detected by immunohistochemical staining and by increased mRNA levels for Dynamin 2 in WB (1.5-fold) and LoVo (2.2-fold) cells. Specific small interference RNA (siRNA) transfection significantly inhibited Dynamin 2 expression in various tumor cell lines (LoVo, D54, and MCF-7) and abolished the radiation induction of Dynamin 2. Likewise, radiation-induced viral gene transfer in these cells (6.5-, 5.5-, and 9.0-fold, respectively) was significantly reduced in siRNA-transfected cells (2.7-, 3.7-, and 5.0-fold, respectively). Moreover, viral uptake in LoVo tumor xenografts was significantly increased in s.c. tumors (10.9-fold) when adenovirus was given i.v. at 24 hours after tumor irradiation, coincident with an elevated Dynamin 2 expression in irradiated tumors. These data suggest that ionizing radiation induces adenovirus gene transfer in cells and tumor xenografts by regulating viral uptake, potentially through interaction with cellular Dynamin 2 and thus should provide insight into improving adenovirus targeting in tumors.

Adenoviridae↗
PubMed2005

Use of magnetic resonance imaging to assess blood-brain/blood-glioma barrier opening during conformal radiotherapy.

PURPOSE: For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas. PATIENTS AND METHODS: Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received. RESULTS: In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation. CONCLUSION: Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.

Adult↗
PubMed2005

Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors.

PURPOSE: To investigate whether intensity-modulated radiotherapy (IMRT), optimized using the generalized equivalent uniform dose (gEUD) and normal tissue complication probability (NTCP) models, can increase the safe dose to intrahepatic tumors compared with three-dimensional conformal RT (3D-CRT). A secondary objective was to investigate the optimal beam arrangement for liver IMRT plans. METHODS AND MATERIALS: Planning CT data of 15 patients with intrahepatic tumors, previously treated with 3D-CRT, were used as input. The dose delivered using 3D-CRT had been limited either by tolerance of adjacent organs, which were close to, or overlapped with, the planning target volume (PTV; overlap cases, n = 8), or liver toxicity (nonoverlap, n = 7). IMRT plans were created using the gEUD to maximize the dose across the PTV and the NTCP to maintain the organ-at-risk toxicity to that of the conformal plan. Increased heterogeneity was allowed across the PTV in overlap cases, without compromising the minimal PTV dose of the conformal plan and restricting the maximal dose to within 110% of the mean. Three different beam arrangements were used for each case: seven-field equidistant axial, six-field noncoplanar (predominantly right-sided beams), and a reproduction of the conformal gantry angles. gEUDs were also computed and used for evaluation of the plans (regardless of planning technique) to reflect the response of both high- and low-grade tumors. The IMRT plan that allowed the greatest gEUD across the PTV was used in the comparison with the 3D-CRT plan. RESULTS: The use of IMRT significantly increased the maximal gEUD achievable across the PTV compared with the 3D-CRT plans. This was the case for the assumptions of both high- and low-grade tumors, irrespective of the tumor position within the liver. The mean gEUD increase was 11 Gy (high grade) and 18.0 Gy (low grade) for overlap cases (p = 0.001 and p = 0.003, respectively) and 10 Gy for nonoverlap cases (p = 0.020). When comparing the IMRT beam arrangements, gEUDs were considered equivalent if they differed by less than one fraction (1.5 Gy). In overlap cases (n = 8), an equivalent "best" gEUD value was obtained in 3, 5, and 7 cases for the original conformal angle, seven-field axial, and six-field noncoplanar plan, respectively. The corresponding results were 5, 2, and 3 in the cases without an overlap (n = 7). CONCLUSION: We have successfully used mathematical/biologic models directly as cost functions within the optimizing process to produce IMRT plans that maximize the gEUD while maintaining compliance with a well-defined protocol for the treatment of intrahepatic cancer. For both PTV-organ-at-risk overlap and nonoverlap situations, IMRT has the capacity to improve the maximal dose achievable across the PTV, expressed in terms of the gEUD. The use of multiple noncoplanar beams appears to confer an advantage over fewer beams in cases with PTV-organ-at-risk overlap. When liver toxicity is the dose-limiting factor, high gEUD values are obtained most frequently when the field arrangement is chosen to provide the shortest possible transhepatic path length.

Algorithms↗
PubMed2005

Determination of WR-1065 in human blood by high-performance liquid chromatography following fluorescent derivatization by a maleimide reagent ThioGlo3.

In order to improve the sensitivity and stability of human blood samples containing WR-1065 (i.e., active metabolite of the cytoprotective agent amifostine), a high-performance liquid chromatographic method was developed and validated using fluorescent derivatization with ThioGlo3. Using a sample volume of only 100 microl, the method was specific, sensitive (limit of quantitation=10 nM in deproteinized blood or 20 nM in whole blood), accurate (error < or = 3.2%) and reproducible (CV < or = 8.7%). In addition, the stability of WR-1065 in deproteinized and derivatized blood samples was assured for at least four weeks at -20 degrees C. This method should be particularly valuable in translating the kinetic-dynamic relationship of WR-1065 in preclinical models to that in cancer patients.

Amifostine↗
PubMed2005

Functional diffusion map: a noninvasive MRI biomarker for early stratification of clinical brain tumor response.

Assessment of radiation and chemotherapy efficacy for brain cancer patients is traditionally accomplished by measuring changes in tumor size several months after therapy has been administered. The ability to use noninvasive imaging during the early stages of fractionated therapy to determine whether a particular treatment will be effective would provide an opportunity to optimize individual patient management and avoid unnecessary systemic toxicity, expense, and treatment delays. We investigated whether changes in the Brownian motion of water within tumor tissue as quantified by using diffusion MRI could be used as a biomarker for early prediction of treatment response in brain cancer patients. Twenty brain tumor patients were examined by standard and diffusion MRI before initiation of treatment. Additional images were acquired 3 weeks after initiation of chemo- and/or radiotherapy. Images were coregistered to pretreatment scans, and changes in tumor water diffusion values were calculated and displayed as a functional diffusion map (fDM) for correlation with clinical response. Of the 20 patients imaged during the course of therapy, 6 were classified as having a partial response, 6 as stable disease, and 8 as progressive disease. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response. Overall, fDM analysis provided an early biomarker for predicting treatment response in brain tumor patients.

Adolescent↗
PubMed2005

Radiotherapy for unresectable hepatic malignancies.

The management of hepatic malignancies, primary or metastatic, is an increasingly common problem in clinical practice. Unfortunately, most patients present with unresectable disease for which there is no universally accepted standard therapy. Radiotherapy is gaining importance in the management of these tumors and in this article we will review the advancements made in this field recently. Increased understanding of the relationship between radiation dose and volume and the risk of radiation-induced liver disease (RILD) has allowed delivery of high-dose focal liver radiation with encouraging results. A recent US phase II trial suggests a radiation dose-dependent improvement in survival when compared to historical controls. Others have reported favorable experience with moderate-dose external-beam radiotherapy, stereotactic hypofractionated radiotherapy, and radiopharmaceuticals.

Carcinoma, Hepatocellular↗
PubMed2005

Radiotherapy: what can be achieved by technical improvements in dose delivery?

The specialty of radiotherapy has changed rapidly over the past two decades with the development of more sophisticated planning and delivery techniques. These techniques have made it possible to increase safely the radiation dose to the tumour while limiting the dose to surrounding healthy tissues that are sensitive to radiation. Here, we focus on clinical improvements that have been achieved with technological advances in the planning and delivery of radiotherapy and look at the potential for future improvements. It should be noted that improved understanding of the biology underlying the radiation response and the use of chemotherapy and molecularly targeted therapy to enhance radiation sensitivity have contributed equally to the improved outcome of patients undergoing radiotherapy.

Humans↗
PubMed2005

Non-small cell lung cancer therapy-related pulmonary toxicity: an update on radiation pneumonitis and fibrosis.

Successful treatment of non-small cell lung cancer requires adequate local and systemic disease control. Although it has been shown to have superior results, high-dose radiation therapy is not a current practice largely because of concerns of normal tissue toxicity. This article reviews and updates the possible mechanism of radiation-induced pneumonitis and fibrosis, their associations with dose intensity, and the role they may play in making treatment decisions. The commonly used clinical terminology and grading systems are summarized. Pneumonitis and fibrosis after 3-dimensional conformal high-dose radiation are reviewed, including recent updates from radiation dose escalation trials. Chemotherapy- and chemoradiation-related lung toxicities are also discussed. Individual susceptibility and potential predictive models are examined; dose and 3-dimensional dosimetric parameters are reviewed along with estimation of normal tissue complication probability and biologic predictive assays. Based on the risk levels of toxicity for each patient, future clinical trials may be designed to maximize individual therapeutic gain.

Antineoplastic Agents↗
PubMed2005

SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing.

Chip profiling of a p53 temperature-sensitive tumor model identified SAK (Snk/Plk-akin kinase), encoding a new member of polo-like kinases (PLKs), as a gene strongly repressed by wild-type p53. Further characterization revealed that SAK expression was downregulated by wild-type p53 in several tumor cell models. Computer search of a 1.7-kb SAK promoter sequence revealed three putative p53 binding sites, but p53 failed to bind to any of these sites, indicating that SAK repression by p53 was not through a direct p53 binding to the promoter. Transcriptional analysis with luciferase reporters driven by SAK promoter deletion fragments identified SP-1 and CREB binding sites, which together conferred a two-fold SAK repression by p53. However, the repression was not reversed by cotransfection of SP-1 or CREB, suggesting a lack of interference between p53 and SP-1 or CREB. Significantly, p53-mediated SAK repression was largely reversed in a dose-dependent manner by Trichostatin A, a potent histone deacetylase (HDAC) inhibitor, suggesting an involvement of HDAC transcription repressors in SAK repression by p53. Biologically, SAK RNA interference (RNAi) silencing induced apoptosis, whereas SAK overexpression attenuated p53-induced apoptosis. Thus, SAK repression by p53 is likely mediated through the recruitment of HDAC repressors, and SAK repression contributes to p53-induced apoptosis.

Amino Acid Sequence↗
PubMed2004

5-fluorouracil and hydroxyurea enhance adenovirus-mediated transgene expression in colon and hepatocellular carcinoma cells.

PURPOSE: To investigate the efficient transduction of tumor cells which remains a major limitation of cancer gene therapy. METHODS: In this study, we tested whether treatment with antimetabolic drugs 5-FU and hydroxyurea (HU) could improve adenovirus-mediated gene expression in tumor cells. RESULTS: We found that 5-FU and HU treatment significantly increased beta-gal activity in adenovirus (Ad.CMVBG)-infected human colon carcinoma (LoVo) and hepatocellular carcinoma (SMMC7721) cells in a dose- and time-dependent manner. These increases were maximized at 5.01+/-0.42-fold and 3.32+/-0.32-fold for 5-FU (50 microM), and at 6.60+/-0.50-fold and 4.82+/-0.43-fold for HU (5 mM) treatment, respectively, after 48 h infection. Transient increases in viral uptake, determined by real-time PCR for viral DNA content and by confocal microscopy for viral particles, were observed in 5-FU or HU-treated cells that partially contribute to the overall increases of beta-gal expression. Moreover, mRNA levels for the beta-gal gene in infected cells were significantly increased in both LoVo and SMMC7721 cells by 5-FU and HU treatment in contrast to the inhibition of viral DNA replication and the unchanged mRNA levels for alpha-actin gene. The induction appeared to be the result of enhanced transcription since beta-gal mRNA half-life was not affected by drug treatment. However, similar induction was not detected in CMV-beta-gal-expressing stable cells, suggesting that an adenovirus-associated mechanism might be involved in this induction. CONCLUSIONS: Our findings suggest that it may be possible to improve tumor cell transduction by adenovirus using chemotherapy.

Adenoviridae↗
PubMed2004

Adjuvant therapy in pancreatic cancer: Phase I trial of radiation dose escalation with concurrent full-dose gemcitabine.

PURPOSE: To determine the maximal tolerated dose of radiation delivered to the primary tumor bed, in combination with full-dose gemcitabine (1000 mg/m(2) weekly x 3), after resection of pancreatic cancer. METHODS AND MATERIALS: Patients with resected pancreatic carcinoma and poor prognostic features, a positive resection margin, or involved lymph nodes were eligible. Radiotherapy (RT) was directed at the preoperative tumor volume with a conformal technique. Regional lymph node basins were not included. The initial starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in 0.2-Gy increments, keeping the duration of RT to 3 weeks. Gemcitabine was given i.v. for 30-40 min at a dose of 1000 mg/m(2) before RT on Days 1, 8, and 15 of a 28-day cycle. After completion of RT and chemotherapy, an additional cycle of gemcitabine was delivered. RESULTS: Between November 1997 and October 2001, 32 patients were entered: 30 after Whipple resection (positive margins in 2, positive nodes in 22, and both in 6), 1 after distal pancreatectomy, and 1 after incomplete resection of a tumor involving the body (both patients with positive margins and nodes). Treatment was well tolerated. Of the 32 patients, 27 completed all protocol therapy and 29 maintained their pretreatment weight within 5%. Five patients experienced dose-limiting toxicity, four with Grade 3 vomiting requiring hospitalization and one fatal toxicity secondary to pneumonia/sepsis. At the final radiation dose level (42 Gy), 2 patients experienced GI dose-limiting toxicity. At the 39-Gy-dose level, 5 of 6 patients were without dose-limiting toxicity. Isolated local or regional progression was documented in 1 patient. Distant progression was documented in 26 of 32 patients (6 with concurrent local or regional progression). The median survival was 16.5 months (95% confidence interval 12.3-19.9) CONCLUSION: The results of our study indicate that the maximal tolerated radiation dose, administered using conformal techniques targeted to the tumor bed, is 39 Gy. In this high-risk population, data on locoregional control suggest that the reduction in radiation dose and field size minimizes toxicity and does not result in excess failures at these sites.

Adenocarcinoma↗
PubMed2004

Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo.

PURPOSE: Overexpression of the ErbB family of receptor tyrosine kinases has been associated with uncontrolled growth of many tumor types and, therefore, presents a promising molecular target for cancer therapy. CI-1033 is a small molecule tyrosine kinase inhibitor that differs from other 4-anilinoquinazolines by being a pan ErbB (instead of epidermal growth factor receptor-specific) irreversible (instead of reversible) inhibitor. Therefore, we investigated the antitumor effect of CI-1033 alone and in combination with ionizing radiation in vitro and in vivo. EXPERIMENTAL DESIGN: We selected three human colon carcinoma cell-lines (LoVo, Caco-2, which express activated epidermal growth factor receptor and ErbB-2 family members, and SW620, which does not), and analyzed the effects of CI-1033 both in vitro and in vivo. For in vivo studies LoVo and Caco-2 cells were implanted s.c. in the flank of nude mice. After the tumor reached approximately 100 mm(3), treatment was initiated with 20 mg/kg of CI-1033 (orally once daily x 5 for 3 successive weeks), radiation treatment (a total of 30 Gy given in 2 Gy once daily x 5 for 3 successive weeks), or a combination of both CI-1033 and radiation treatment. RESULTS: We found that exposure of LoVo and Caco-2, but not SW620 cells, to CI-1033 in the range of 1-3 micro M could inhibit constitutive signaling by tyrosine kinases, arrest cell growth, inhibit cells in G(1), stimulate expression of p53, and induce apoptosis. The inhibition of cell growth by CI-1033 seemed to produce only minimal radiosensitization in LoVo and Caco-2 cells. In contrast, the combination of CI-1033 and radiation produced significant (P < 0.0005 and P = 0.0002, respectively) and prolonged suppression of tumor growth in both the tumor types when compared with either treatment alone. CONCLUSIONS: These findings suggest that CI-1033 can increase the effectiveness of radiation therapy. The extent of suppression of tyrosine kinase activity by CI-1033, rather than the amount of activity in untreated cells, seemed to be more closely associated with the efficacy of combination treatment.

Animals↗
PubMed2004

The use of 19F spectroscopy and diffusion-weighted MRI to evaluate differences in gene-dependent enzyme prodrug therapies.

To evaluate noninvasive measures of gene expression and tumor response in a gene-dependent enzyme prodrug therapy (GDEPT), a bifunctional fusion gene between Saccharomyces cerevisiae cytosine deaminase (CD) and Haemophilus influenzae uracil phosphoribosyltransferase (UPRT) was constructed. CD deaminates 5-fluorocytosine (5FC) to 5-fluorouracil (5FU), and UPRT subsequently converts 5FU to fluorouridine monophosphate, and both of these reactions can be monitored noninvasively in vitro and in vivo using 19F magnetic resonance spectroscopy (MRS). Following transient transfection the CD-UPRT fusion protein exhibited both UPRT and CD enzymatic activities as documented by 19F MRS. In addition, an increase in CD activity and thermal stability was witnessed for the fusion protein compared to native CD. Stable expression of CD-UPRT in 9L glioma cells increased both 5FC and 5FU sensitivity in vitro compared to CD-expressing and wild-type 9L cells. Noninvasive 19F MRS of both CD and UPRT gene function in vivo demonstrated that in animals bearing CD-expressing tumors there was limited conversion of 5FC to 5FU with no measurable accumulation of cytotoxic fluorinated nucleotides (F-nucs). In contrast, CD-UPRT-expressing tumors had increased CD gene activity with a threefold higher intratumoral accumulation of 5FU and significant generation of F-nucs. Finally, CD-UPRT yielded increased efficacy in an orthotopic animal model of high-grade glioma. More importantly, early changes in cellular water mobility, which are felt to reflect cellular death, as measured by diffusion-weighted MRI, were predictive of both durable response and increased animal survival. These results demonstrate the increased efficacy of the CD-UPRT GDEPT compared to CD alone both biochemically and in a preclinical model and validate both 19F MRS and diffusion-weighted MRI as tools to assess gene function and therapeutic efficacy.

Animals↗