| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery[S. G. S., J. A. R., J. G., A. M. C., M. D., R. F., J. B. P., A. J. S., W. R. S., A. A. V., G. L. W., M. Y.], Department of Radiation Therapy [R. K., Z. L., C. S.], Department of Diagnostic Imaging [M. H., K. A., F. M., R. Mu., T. S.], and Department of Pathology [J. Y. R., A. K. E-N., B. K.], and Department of Thoracic/Head and Neck Medical Oncology [W. K. H., F. F., B. G., R. H., F. R. K., J. M. K., R. Mo., V. P., K. M. W. P., D. M. S.], Department of Pulmonary Medicine [A. H.]; Department of Molecular Pathology and Research [T. J. M.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Introgen Therapeutics, Inc., Houston, Texas 77030 [J. A. M.]; Department of Biomathematics [J. J. L., N. E. A.]; Aventis, Bridgewater, New Jersey [L. D.]; Biotechwrite: Biomedical and Science Communications, Houston, Texas 77079 [S. G.];
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Experimental Design: Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32.
Results: Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment.
Conclusions: Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Because of the apparent links between p53 and apoptosis and between apoptosis and radiation, we extended our previous studies of Ad-p53 gene therapy in NSCLC and initiated a clinical trial of Ad-p53 (INGN 201) combined with external beam ionizing radiation. We report successful gene transfer, low toxicity, and evidence of tumor regression. In addition, we examined the effects of Ad-p53 (INGN 201) in combination with radiation on cell function by examining expression of several genes known to be regulated by p53: p21 (CDKN1A), FAS, BAK, and MDM2. BAK expression, alone, was significantly increased 24 h after injection of Ad-p53 (INGN 201) and thus appeared to be the marker most acutely up-regulated by Ad-p53 (INGN 201), providing the first demonstration of the induction of an apoptotic pathway by tumor suppressor gene expression in actual human cancers.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Gene Transfer Vector.
Ad-p53 (INGN 201) was supplied by Introgen Therapeutics, Inc. (Houston, TX), in frozen aliquots containing 1 x 1012 vp/ml in PBS containing 10% glycerol. Construction and generation of the vector was reported previously (9)
. Briefly, a replication defective adenovirus serotype 5 was constructed by replacing the viral E1 region with a p53 expression cassette consisting of a wild-type p53 gene flanked by the cytomegalovirus promoter and the SV40 polyadenylation signal (9)
.
Eligibility Criteria and Treatment Protocol.
Patients enrolled in the study had histologically proven nonmetastatic NSCLC (stage I–III) with measurable disease. Patients were ineligible for chemoradiation or surgery because of significant comorbidities, age, or obstructed bronchi. Initial treatment with radiotherapy was judged to be the accepted standard of care. The presence of a p53 mutation in the tumor was not a requirement for study entry.
Study treatment consisted of intratumoral needle injections of Ad-p53 (INGN 201) on days 1, 18, and 32 of treatment in an outpatient setting. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy and was directed at the primary tumor and mediastinal lymph nodes if involved. Vector administration was performed by intratumoral injection of the primary tumor either through a flexible bronchoscope or by CT guided percutaneous needle as previously described (10)
. Tumors 
4 cm in the largest diameter were injected with 10 ml divided into three separate sites, whereas tumors with a diameter of <4 cm were injected in a single site with 3 ml. Ad-p53 doses were escalated initially in cohorts of three for the first 9 patients (3 x 1011, 1 x 1012, and 3 x 1012 vp of Ad-p53). All subsequent patients received the highest dose (3 x 1012 vp). Core biopsies were obtained from indicator lesions on days 1, 18, 19, and 32 and 3 months after treatment.
Response and Toxicity.
The toxic effects of therapy were evaluated according to the National Cancer Institute’s Common Toxicity Criteria (11)
. An independent Data Monitoring Committee whose members were not affiliated with either the University of Texas M. D. Anderson Cancer Center or the sponsor of the trial assessed response to therapy. Assessments were made of overall response (including metastatic sites) and response of the injected tumor (excluding metastatic disease). The Data Monitoring Committee used standard criteria with CT and bronchoscopic findings and not pathologic biopsies (12)
. Response of the primary injected tumor focused only on the primary tumor, excluding progression at metastatic sites.
Survival duration was measured from beginning of therapy to date of last follow-up or death. Time to progression for metastatic (pleural effusions, pulmonary nodules, systemic metastases) and locoregional disease (primary tumor and mediastinal or hilar lymph nodes) was defined as the time from beginning of therapy to documented progression. Patients who did not demonstrate progression were censored at the time of last follow-up.
Radiation Therapy.
External radiation therapy was given by linear accelerator 18 or 6 Mv with a total dose of 60 Gy calculated at the isocenter in 30 fractions over 6 weeks without inhomogeneity correction. The margins ranged from 2 to 2.5 cm around the gross target volume.
Real-Time PCR and Reverse Transcription-PCR.
Probes and primers used in this study were designed using the Primer Express software (version 1.0; Perkin-Elmer). Sequences are available upon request. To avoid amplification of contaminating residual genomic DNA, probe and primer sets for each gene were designed around the junction region of two exons so that they are mRNA-specific.
To determine the copy number of Ad-p53 virus in each cell, viral DNA extracted from Ad-p53 was used as an absolute standard, and the ß-actin gene was used as a reference gene to count cell numbers. Briefly, calculation of p53 virus copy number was accomplished by plotting a ß-actin standard curve, using human genomic DNA (from Perkin-Elmer) as a standard (1 ng of DNA equals 
303 genome equivalents) and comparing the results of the clinical samples with the standard using ß-actin probes. This resulted in the number of genomes (cells) in each sample. The number of p53 virus copies in each sample was determined by comparing with a separate p53-virus standard curve (plotted using p53-viral DNA standard.) This value was corrected for the presence of inflammatory cells.
For quantitative real-time reverse transcription-PCR, human total RNA was used as a relative standard and human GAPDH gene served as an internal control for relative mRNA amount. Real-time PCR was performed in the ABI Prism 7700 Sequence Detection System according to the manufacturer’s protocol.
Statistical Considerations.
The purpose of this nonrandomized Phase I/II study was to evaluate the efficacy of Ad-p53 (INGN 201) gene therapy as an adjunct to radiation therapy in the treatment of patients with NSCLC. The primary end point for evaluation was the local control of tumor at 3 months. The study was designed to test the null hypothesis that the 3-month local control rate is 20% versus the alternate hypothesis that the rate is 40% using a one-sided exact binomial test with an 
level of 5%. The sample size of 49 patients provided a power of 83%. An interim analysis after 15 patients was included in the design.
Data from 17 of 19 patients enrolled in this study were analyzed. For each patient, the gene expression for p53 and GAPDH were measured in duplicate at four distinct time points: time 0 = baseline, before any therapy; time 1 = on day 18 after the first Ad-p53 (INGN 201) injection and after 2 weeks of radiation therapy but before the second Ad-p53 (INGN 201) injection; time 2 = on day 19, 24 h after the second Ad-p53 (INGN 201) injection and after 2 weeks of radiation therapy; and time 3 = at day 32, before the third Ad-p53 (INGN 201) injection and after 4 weeks of radiation therapy. Ratio of the marker gene and GAPDH was calculated to estimate the amount of target gene expression. The coefficient of variation (defined as SD divided by the mean) was computed to estimate the precision of the duplicate experiment. Modulation of gene expression over time was assessed by comparing the ratios of the target gene between two time points. Exact binomial test was applied to test the null hypothesis of no modulation by assuming that the probability of up-regulation (or down-regulation) equals to 0.5. Two-sided Ps were calculated. Duplicate experiments were done when adequate tissue samples were available (patients 16, 15, 13, 12, and 11 at time 0, 1, 2, and 3, respectively). The coefficient of variation ranged from 0 to 1.21 with a median of 0.2. There were 78 and 97% of the samples with coefficient of variation < 0.5 and 0.8, respectively, indicating good reproducibility between the duplicate experiments. The precision was similar among all four time points.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
between April 30, 1998, and May 4, 2000. The date of last follow-up was April 1, 2002, with a median follow-up of 36 months. All patients had histologically determined viable NSCLC on pretreatment tumor biopsies. Nine patients had locoregionally advanced NSCLC (5 stage IIIA and 4 stage IIIB) and were ineligible for chemoradiation because of poor performance status, age, comorbidities, or obstructed bronchi. Ten patients with stage I and II NSCLC (2 stage IA, 5 stage IB, and 3 stage IIB) were ineligible for surgery because of poor pulmonary function tests or significant comorbidities.
|
). Seventeen of 19 patients received all planned treatment, whereas 2 patients did not complete therapy because of tumor progression (patient no. 18) or early death (patient no. 6). Two additional patients did not receive tumor biopsies 3 months after completion of therapy because of tumor progression (patient no. 10) or weakness (patient no. 19). The presence of a p53 mutation in the primary tumor was not required for entry into the study because previous studies in animal models, as well as in clinical trials, have shown no clear relationship between p53 mutational status and response to INGN 201 treatment (10
, 13, 14, 15)
.
Seventeen of 19 patients completed the radiation therapy according to the protocol with a total tumor dose of 60 Gy in 30 fractions (2 Gy/day) by high energy (6 Mv) accelerated photons. The duration of the radiation therapy ranged from 39 to 50 days with the median duration as 44 days. There were no major protocol violations such as prolonged interruption of radiation therapy or administration of nonstudy anticancer therapy among the 17 patients.
Antitumoral Efficacy.
Three months after completion of radiation therapy and Ad-p53 (INGN 201) therapy, antitumoral efficacy was determined with CT scan evaluation (16 of 19 patients) and pathologic examination of biopsies (15 of 19 patients). Pathologic examination of biopsies 3 months after completion of therapy revealed no viable tumor in 12 patients (12 of 19, 63%) and viable tumor in 3 of 19 patients (16%). Tumors of 4 patients (4 of 19, 21%) were not biopsied because of tumor progression (patients nos. 10 and 18), early death (patient no. 6), or weakness (patient no. 19). The study was closed to additional accrual after the planned interim analysis after 19 patients.
Assessment of the primary injected tumor 3 months after completion of therapy (Table 1
, Fig. 1, A and B
) was performed by an external review board with CT and bronchoscopic findings and demonstrated: a CR in 1 patient (1 of 19, 5%); PR in 11 patients (11 of 19, 58%); stable disease in 3 patients (3 of 19, 16%); and PD in 2 patients (2 of 19, 11%). Two patients (2 of 19, 11%) were nonevaluable because of tumor progression (patient no. 18) or early death on treatment day 69 (patient no. 6).
|
. Five patients are currently alive without evidence of disease 34–48 months after the start of treatment. Eleven patients have developed clinically diagnosed distant metastases (5 pleural effusions, 2 pulmonary nodules, 1 bone, 1 brain, 1 brain, and s.c. nodules and 1 adrenal). Median time to progression has not been reached (Fig. 2B)
for locoregional disease and is 9.2 months for metastatic disease (Fig. 2C)
.
|
). All pneumothoraces were managed on an outpatient basis, with observation or percutaneous catheters. Radiation therapy was associated with primarily grade 1 or 2 esophagitis (47%), anorexia (21%), or weakness (58%). Grade 3 (severe) or grade 4 (life threatening) toxicity was noted in 6 of 19 (33%) patients and consisted of atrial arrhythmias, anemia, weakness, anorexia, pain, nausea, dyspnea, confusion, hypotension, and hallucination. The combination of Ad-p53 (INGN 201) and radiation therapy did not appear to increase toxicity over what was expected with radiation therapy alone based on previous experience (16
, 17) . No patients discontinued radiation therapy or Ad-p53 (INGN 201) because of treatment-related adverse events. In addition, no treatment related deaths were observed.
|
by quantitative real-time PCR in preinjection (day 18 after entry into the protocol) and 24 h after injection (day 19) biopsy specimens. The ß-actin genome number is given in the table in parentheses as a positive control to show the presence of DNA in the sample. All values were corrected for the percentage of nontumor cells present in the biopsy.
|
Effect of Ad-p53 (INGN 201) Gene Transfer on mRNA Expression of p53-regulated Genes.
Previous in vitro experiments in human NSCLC cell lines identified four genes [p21 (CDKN1A), MDM2, FAS, and BAK] that showed the greatest increase in mRNA expression after induction of p53 overexpression with Ad-p53 (data not shown). Therefore, in the current study, changes in mRNA levels for these four markers were determined at various time points before and during treatment using reverse transcriptase real-time PCR (Table 4)
. The study was controlled by obtaining a pretreatment biopsy under the same conditions as the posttreatment biopsy. The inclusion of a time point during the radiation treatment allowed for a biopsy to be performed immediately before and 24 h after Ad-p53 injection, thus allowing determination of the effects of the Ad-p53 on mRNA expression during treatment. An increase in mRNA expression was defined as a ratio >2 compared with GAPDH; a decrease was defined as a ratio <0.5; any value between 0.5 and 2 was considered no change. The exact binomial two-sided test was used to test the null hypothesis of no modulation between time points. The time intervals in Table 4
refer to: (a) change between day 18 (immediately before injection) and day 19 [24 h after Ad-p53 (INGN 201) injection]; and (b) change between day 0 (before initiation of all treatment) and days 18, 19, and 32 (days after initiation of treatment).
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, which may have been expected because chemotherapy could not be administered to these high-risk patients. In future studies, we plan to address metastatic relapse by adding chemotherapy to the combination of Ad-p53 (INGN 201) and radiation therapy. It is encouraging that strategies designed to improve locoregional control in locoregionally advanced NSCLC such as concurrent chemoradiation or fractionated radiation therapy have led to improved survival (17, 18, 19) . The Japanese Clinical Oncology Group and the Radiation Therapy Oncology Group recently reported improved survival in locoregionally advanced NSCLC when concurrent chemoradiation rather than sequential chemoradiation was used, presumably because of the radiation sensitizing effect of concurrent chemotherapy (19, 20, 21) , although toxicity appeared increased with concurrent chemotherapy. Additionally, subset analysis of these studies have demonstrated that concurrent chemoradiation might not be as effective in elderly or poor performance status patients, in part, because of increased toxicity (22) . These observations suggest a therapeutic window for Ad-p53 (INGN 201) and radiation therapy because this novel strategy demonstrated no dose-limiting toxicity with concurrent use and was limited only by manufacturing considerations. Although these patients were often ineligible for chemoradiation because of age or significant comorbidities, only 34% of the patients suffered a grade 3 or higher adverse event, and all patients were treated as outpatients. In the future, Ad-p53 (INGN 201) may, in combination with chemoradiation, provide enhanced survival by increasing locoregional control without increasing toxicity.
Another major goal of this study was to determine the molecular mechanism by which Ad-p53 (INGN 201) and radiation therapy-induced cell killing. We therefore performed multiple biopsies throughout the study to evaluate the time course of the induction of several apoptosis-related genes and their relationship to p53 gene transfer and radiation therapy. We demonstrated for the first time in human cancers in situ, the induction of expression of several genes closely linked to p53, including MDM2, p21 (CDKN1A), and BAK. Our study showed that, although p21 (CDKN1A) and MDM2 appeared to be modestly up-regulated in tumors injected with Ad-p53 (INGN 201), it was the proapoptotic gene BAK that showed significant up-regulation within 24 h of Ad-p53 (INGN 201) injection. Because of the study design, it remains possible that radiation alone had an effect on the marker genes independent of Ad-p53 (INGN 201) administration. A study by Bishay et al. (23) , however, showed that BAK mRNA remains at a constant level in cells with endogenous wt-p53 after radiation. Thus, our observation of an increase in BAK links this specifically to the forced overexpression of p53 by Ad-p53 (INGN 201) gene transfer. Previously, Pearson et al. (24) showed up-regulation of BAK protein expression in lung cancer cell lines in response to forced overexpression of p53. Bishay et al. (23) also showed increased expression of p21 (CDKN1A) in B lymphoblastoid cells, suggesting that radiation in the presence of wt-p53 can induce p21 (CDKN1A) expression. However, in our study, this cannot be specifically attributed to forced overexpression of p53 because radiation can achieve this with low levels of wt-p53. In lung tumors with nonfunctional wt-p53, which likely includes most of tumors in our study, the restoration of wt-p53 function probably contributed to the increases in p21 (CDKN1A) expression.
The role of these genes in mediating tumor regression and apoptosis in patients will require further study. However, previous studies have shown conclusively that forced overexpression of p53 by both retroviral and adenoviral vectors is associated with marked increases in the apoptotic fraction of NSCLC cells in biopsies taken 72 h after injection of Ad-p53 as shown by terminal deoxynucleotide transferase-mediated biotin UTP nick-end labeling staining (10 , 13 , 25) . The up-regulation of the proapoptotic gene BAK may, in part, be responsible for this effect, although this study cannot determine whether Ad-p53 was responsible because radiation was administered simultaneously. Although many genes may be under the regulatory control of p53, we initially screened several NSCLC cell lines for those apoptosis-associated genes most strongly up-regulated by forced p53 overexpression. Thus, although our study does not include all known p53 regulated genes, it provides important confirmation of the cell culture findings and a methodology for future studies.
Future clinical trials will explore the combination of Ad-p53 (INGN 201) gene transfer and chemoradiation to address both metastatic and locoregional disease. The antitumoral potential of these strategies is supported by preclinical data that suggests the combination of all three treatments (Ad-p53, chemotherapy, and radiation therapy) is synergistic and may lead to enhanced antitumoral activity without increased toxicity.4 This study has been an important foundation for future studies because it provides a molecular mechanism for the enhanced antitumoral activity with sequential tumor biopsies and quantitative analysis of p53-regulated genes. It confirms that after Ad-p53 (INGN 201) gene transfer and radiation therapy, wt-p53 gene expression increases dramatically with subsequent induction of BAK, MDM2, and p21 (CDKN1A). In the future, these molecular markers may help clinicians to identify those patients most likely to respond to Ad-p53 (INGN 201) gene transfer strategies.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
2 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, #445, Houston, TX 77030. Phone: (713) 792-8659; E-mail: sswisher{at}mdanderson.org
3 The abbreviations used are: NSCLC, non-small cell lung cancer; vp, viral particles; CT, computed tomography; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; wt-p53, wild-type p53.
Received 5/17/02; revised 8/13/02; accepted 8/20/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
irradiation of a human lymphoblastoid cell line. Oncogene, 19: 916-923, 2000.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  L. Wu, Z. Li, Y. Zhang, P. Zhang, X. Zhu, J. Huang, T. Ma, T. Lu, Q. Song, Q. Li, et al. Adenovirus-expressed human hyperplasia suppressor gene induces apoptosis in cancer cells Mol. Cancer Ther., January 1, 2008; 7(1): 222 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Senzer, J. Nemunaitis, M. Nemunaitis, J. Lamont, M. Gore, H. Gabra, R. Eeles, N. Sodha, F. J. Lynch, L. A. Zumstein, et al. p53 therapy in a patient with Li-Fraumeni syndrome Mol. Cancer Ther., May 1, 2007; 6(5): 1478 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dvory-Sobol, E. Sagiv, D. Kazanov, A. Ben-Ze'ev, and N. Arber Targeting the active {beta}-catenin pathway to treat cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2861 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Cross and J. K. Burmester Gene therapy for cancer treatment: past, present and future. Clin. Med. Res., September 1, 2006; 4(3): 218 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Tolcher, D. Hao, J. de Bono, A. Miller, A. Patnaik, L. A. Hammond, L. Smetzer, J. Van Wart Hood, J. Merritt, E. K. Rowinsky, et al. Phase I, Pharmacokinetic, and Pharmacodynamic Study of Intravenously Administered Ad5CMV-p53, an Adenoviral Vector Containing the Wild-Type p53 Gene, in Patients With Advanced Cancer J. Clin. Oncol., May 1, 2006; 24(13): 2052 - 2058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Fujiwara, N. Tanaka, S. Kanazawa, S. Ohtani, Y. Saijo, T. Nukiwa, K. Yoshimura, T. Sato, Y. Eto, S. Chada, et al. Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., April 10, 2006; 24(11): 1689 - 1699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhang, R. M. Cheung, R. Komaki, B. Fang, and J. Y. Chang Radiotherapy Sensitization by Tumor-Specific TRAIL Gene Targeting Improves Survival of Mice Bearing Human Non-Small Cell Lung Cancer Clin. Cancer Res., September 15, 2005; 11(18): 6657 - 6668. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. M. Ghobrial, T. E. Witzig, and A. A. Adjei Targeting Apoptosis Pathways in Cancer Therapy CA Cancer J Clin, May 1, 2005; 55(3): 178 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hoti, D.-e Zhu, Z. Song, Z. Wu, S. Tabassum, and M. Wu p53-Dependent Apoptotic Mechanism of a New Designer Bimetallic Compound Tri-phenyl Tin Benzimidazolethiol Copper Chloride (TPT-CuCl2): In Vivo Studies in Wistar Rats as Well as in Vitro Studies in Human Cervical Cancer Cells J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 22 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S M Selkirk Gene therapy in clinical medicine Postgrad. Med. J., October 1, 2004; 80(948): 560 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Barzon, M. Boscaro, and G. Palu Endocrine Aspects of Cancer Gene Therapy Endocr. Rev., February 1, 2004; 25(1): 1 - 44. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ohtani, S. Kagawa, Y. Tango, T. Umeoka, N. Tokunaga, Y. Tsunemitsu, J. A. Roth, Y. Taya, N. Tanaka, and T. Fujiwara Quantitative analysis of p53-targeted gene expression and visualization of p53 transcriptional activity following intratumoral administration of adenoviral p53 in vivo Mol. Cancer Ther., January 1, 2004; 3(1): 93 - 100. [Abstract] [Full Text]
|
|
|
|
|
|
N. K. Sah, A. Munshi, T. Nishikawa, T. Mukhopadhyay, J. A. Roth, and R. E. Meyn Adenovirus-mediated wild-type p53 radiosensitizes human tumor cells by suppressing DNA repair capacity Mol. Cancer Ther., November 1, 2003; 2(11): 1223 - 1231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hoti, J. Ma, S. Tabassum, Y. Wang, and M. Wu Triphenyl Tin Benzimidazolethiol, a Novel Antitumor Agent, Induces Mitochondrial-Mediated Apoptosis in Human Cervical Cancer Cells via Suppression of HPV-18 Encoded E6 J. Biochem., October 1, 2003; 134(4): 521 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fukazawa, B. Walter, and L. B. Owen-Schaub Adenoviral Bid Overexpression Induces Caspase-dependent Cleavage of Truncated Bid and p53-independent Apoptosis in Human Non-small Cell Lung Cancers J. Biol. Chem., July 3, 2003; 278(28): 25428 - 25434. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS |
