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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2052-2058 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.6756 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
From the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX; Introgen Therapeutics Inc, Houston, TX Address reprint requests to Anthony W. Tolcher, MD, FRCP(C), Institute for Drug Development, Cancer Therapy and Research Center, 7979 Wurzbach Suite Z414, San Antonio, TX 78229; e-mail: atolcher{at}idd.org
PURPOSE: The purpose of this study was to assess the feasibility of administering Ad5CMV-p53, an adenoviral vector containing the wild-type p53 gene to patients with advanced malignancies, characterize the pertinent pharmacokinetic parameters, identify evidence of viral uptake in both normal and tumor tissue, and seek evidence of antitumor activity. METHODS: Patients were treated with escalating doses of Ad5CMV-p53 intravenously over 30 minutes on days 1, 2, and 3, every 28 days. The clearance of circulating Ad5CMV-p53 (INGN 201) DNA was characterized in the plasma and paired tumor and skin biopsies were performed in patients treated at the two highest dose levels to assess vector uptake into tissues. RESULTS: Seventeen patients received 36 courses of Ad5CMV-p53 at doses ranging from 3 x 1010 to 3 x 1012 virus particles (vp). Fatigue, nausea, vomiting, and fever were common, but rarely severe. Abnormalities of coagulation parameters, including decreases in fibrinogen and increases in fibrin degradation products at 3 x 1012vp, precluded additional dose escalation. Ad5CMV-p53 DNA could be detected in the plasma by polymerase chain reaction assay in the majority of patients at 14 days and 28 days at doses of 3 x 1010 and higher. Six patients treated at 1 x 1012vp and 3 x 1012vp dose levels had Ad5CMV-p53 DNA detected within paired tumor tissue collected day 4. CONCLUSION: Ad5CMV-p53 can be safely and repetitively administered up to 1 x 1012vp intravenously daily for 3 consecutive days. The absence of severe toxicities, the presence of circulating adenovirus 24 hours after administration, and detectable p53 transgene within tumor tissue distant from the site of administration demonstrates that systemic therapy with this adenoviral vector containing p53 is feasible.
The p53 gene encodes a 53-kD phosphoprotein that regulates cell cycle transit as well as genomic integrity.1,2 In the event of DNA damage, wild type (wt) p53 functions to induce G1 arrest and initiate DNA repair, or alternatively induce apoptosis.3 Mutations at multiple sites within the p53 gene have been described either through frame-shift chain terminating mutations, or more commonly, missense mutations that increase the stability of the protein but loss of function.4 Aberrant p53 protein has been described in approximately 50% of solid tumors and is correlated with poor clinical prognosis in a broad spectrum of malignancies.5-9 Ad5CMV-p53 (INGN 201; ADVEXIN; Introgen Therapeutics Inc, Houston, TX) an adenoviral vector containing the wt p53 gene is a replication defective (E1-, E3-partially depleted) type-5 adenovirus vector that contains a cytomegalovirus (CMV) promoter and a wtp53 gene construct.10 In preclinical studies, transduction of wt p53 by Ad5CMV-p53 into human tumor cell lines containing p53 mutations induced p53 protein expression and apoptosis.11-13 Furthermore, direct injection of Ad5CMV-p53 into human tumors implanted into immuno-incompetent mice induced regressions and increased survival.14,15 Ad5CMV-p53 has previously been investigated in phase I/II studies utilizing direct intratumoral injection.16-20 While dose limiting toxicities and a maximum-tolerated dose (MTD) were not determined at doses up to 3 x 1012 virus particles (vp) when injected intratumorally, systemic symptoms were observed, including fever, fatigue, and nausea. Moreover, despite the injection of Ad5CMV-p53 directly into tumor sites, evidence in preclinical models and human clinical studies indicate that some systemic distribution occurs with Ad5CMV-p53 DNA detected in the plasma, viral particles excreted in urine, and an increase in antiadenoviral antibody titers.16,19 Systemic dissemination and the complications of metastases are the most frequent causes of deaths due to malignancy. Furthermore, most metastases are not accessible for direct local injection. The systemic administration of a vector that introduces wt-p53 into distant metastases would therefore be a significant advance and provided the impetus to examine the systemic administration of Ad5CMV-p53. The principal objectives of this phase I, pharmacokinetic, and biologic correlative study were to: determine the feasibility of intravenous administration of Ad5CMV-p53 daily for 3 consecutive days every 4 weeks; characterize the toxicities of systemically administered Ad5CMV-p53; characterize the clearance of Ad5CMV-p53; examine evidence of wt-p53 transduction in normal and tumor tissue biopsies; and seek preliminary evidence of antitumor activity in patients.
Patient Selection Patients with advanced malignancies refractory to curative therapy or in whom no effective therapy existed were eligible and tumor p53 status was not required. All patients had an age  18 years; life-expectancy 12 weeks; an Eastern Cooperative Oncology Group performance status of 0 to 2; chemotherapy completion 4 weeks prior (6 weeks for prior mitomycin C or a nitrosourea); negative serology for hepatitis B, C, and HIV; hemoglobin 9 g/dL; ANC 1500/µL; WBC 3000/µ L; platelet count 100,000/µL; bilirubin value, AST, and ALT  .5 x institutional upper limit of normal; and alkaline phosphatase 3 x upper limit of normal; creatinine 1.5 mg/dL; and no coexisting medical problems that limit compliance. Patients with CNS metastases, primary CNS tumors, prior gene therapy, concomitant antiviral therapy or active infections were ineligible. Patients gave written informed consent for all clinical and research aspects of the study according to federal and institutional guidelines before treatment and was approved by the appropriate institutional review board.
Drug Administration
Advexin (Ad5CMV-p53) was supplied by Introgen Therapeutics as single use 1 mL glass vials containing a frozen viral suspension in Dulbecco's phosphate-buffered saline and 10% (v/v) glycerol. The appropriate dose was stored at
Pretreatment and Follow-Up Studies
Plasma Pharmacokinetic Sampling and Polymerase Chain Reaction Assay The polymerase chain reaction (PCR) assay for Ad5CMV-p53 detection in the plasma has been previously described.21 Briefly, 200 µ L aliquots of plasma obtained from patients were assayed and compared with a standard curve constructed with a series of dilutions of control DNA extract. Semi-quantitative values were obtained from the cycle number (CT) at which an increase in the fluorescent signal associated with exponential growth of PCR products started to be detected by the laser detector of the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA). The PCR cycling program consisted of one cycle at 50°C for 2 minutes, and at 95°C for 10 minutes, 50 cycles comprising 95°C for 15 seconds (denaturation), and 65°C for 1 minute (annealing and extension), then one cycle at 25°C for 10 minutes.
The criteria for detection was a CT value of
Detection of Ad5CMV-p53 DNA in Tumor, Skin Biopsy Specimens, Urine, Oral Rinses, and Rectal Swabs Serial oral rinses, urine, and rectal swab specimens were collected from patients during each course of therapy and assayed using the PCR assay described above.
Detection of Neutralizing Antibodies Directed to Adenovirus 5
General Seventeen patients, whose demographics are displayed in Table 1, received 36 courses of Ad5CMV-p53 at doses ranging from 3 x 1010 to 3 x 1012 vp. The number of patients and courses at each dose level, as well as the overall dose escalation scheme, are depicted in Table 2. The median number of courses administered per patient was two (range, 1 to 10). The dose was reduced in only one patient.
After negligible drug-related effects were observed at 3 x 1010 vp (Tables 3 and 4), the Ad5CMV-p53 dose was increased to 1 x 1011 vp. The first patient treated at this dose experienced a grade 3 AST elevation that was attributed to progressive disease. To better characterize the safety at this dose, two additional patients were entered and no additional grade 2 or greater abnormalities occurred. Dose-escalation continued to 3 x 1011 vp, and the 1 x 1012 vp dose level. At this latter dose a constellation of grade 2 toxicities occurred including fever, fatigue, emesis, leukopenia, and diarrhea that precluded additional single patient cohorts. One patient subsequently entered at this dose level experienced dose-limiting grade 3 fatigue with diarrhea requiring the cohort expansion to 6 patients without additional DLTs. Two of six patients treated at the next highest dose, 3 x 1012 vp, experienced asymptomatic, transient elevations of PTT (grade 1 and grade 3) and one of these patients demonstrated elevation in FDP consistent with grade 3 disseminated intravascular coagulation. On the basis of these results, Ad5CMV-p53 can be feasibly administered at 3 x 1012 vp IV; however, to avoid significant alterations of coagulation parameters, the recommended dose is 1 x 1012 vp daily for 3 days every 28 days.
Safety Coagulation and hematology toxicities. The principal DLT was the aforementioned clinically asymptomatic and reversible rise in PTT values, and in one patient an grade 3 elevation (between 5 and 20 u, normal < 5 u) in FDP. In the first two patients entered at the 3 x 1012 vp dose level, the increase in PTT values occurred at days 6 and 7 and remained elevated until day 15 before returning to pretreatment values before day 28. This was not accompanied by an increase in international normalized ratio nor clinical evidence of bleeding. In one patient treated at the 3 x 1012 vp dose level, an elevation of PTT recurred after course two day 1, day 2 treatment was then held, resolved by course two day 3 and Ad5CMV-p53 administration was reinstituted on day 3 but was followed by a near two-fold elevation of PTT compared to baseline by day 4. Although this constituted a grade 1 elevation of PTT, this patient was subsequently dose reduced for subsequent courses without additional elevation of PTT values. One additional patient had an elevation of FDP (to 40 u) by day 2 course two. This patient did not receive any additional Ad5CMV-p53 infusions. The distributions and the relevant grades of leukopenia, thrombocytopenia, and anemia as a function of dose are listed in Table 3. Myelosuppression and thrombocytopenia were not considered related to Ad5CMV-p53 treatment. Nonhematologic toxicities. The predominant nonhematologic toxicities related to treatment were fever, chills, fatigue, diarrhea, myalgias, arthralgias, nausea, and vomiting, were mild or modest (grade 1 and 2) in intensity and are summarized in Table 4. Fever was not documented at the two lowest dose levels, but was near universal at the next three higher doses of Ad5CMV-p53 and twelve patients (71%) experienced fever, often accompanied by chills, during the first course of therapy. Fatigue was observed in eight patients (47%) whereas vomiting occurred in six patients (35%) that was severe (grade 3) in one patient at the highest dose level (course 2). Elevations in hepatic transaminases were infrequent. During course one, a colon carcinoma patient with hepatic metastases treated at 3 x 1010 vp had an AST elevation from grade 1 to 3 after the first course, attributed to progressive disease. One additional patient during course two at the 3 x 1012 vp dose level experienced an elevation of AST to grade 2 from a grade 1 accompanied by a grade 3 elevation in lactate dehydrogenase. This was the same aforementioned patient with the elevation in FDP observed during the same course.
Pharmacokinetics and Pharmacodynamics
Detection of Ad5CMV-p53 DNA Expression in Tumor Tissue, Skin Biopsies Urine, Rectal Swabs, and Oral Rinses Eleven of 12 patients treated at the 1 x 1012 and 3 x 1012 vp dose levels underwent tumor biopsies. Only seven of 11 patients had paired (pre- and post-treatment) tumor biopsy samples assessable for Ad5CMV-p53 expression. Six of seven (86%) patients had undetectable Ad5CMV-p53 expression pretreatment that became detectable after treatment (Fig 1). Due to toxicity, one patient who did not have a post-treatment tumor biopsy on day 4 subsequently had a biopsy on course two day 4. Post-treatment biopsies were not performed or assessable in three patients, and one patient had a post-treatment biopsy only (mean, 1,517 copies/µg DNA). There was no relationship between dose and number of copies of Ad5CMV-p53 detected in tumor biopsies.
Only four of seven patients had skin biopsies assessable for Ad5CMV-p53 DNA expression. In three of four patients Ad5CMV-p53 DNA was not detected in the skin. In one patient, p53 transgene DNA was detected in the skin day 4 following IV treatment, but the copy number was lower than the matched tumor biopsy (674 copies v 2,033 copies p53 per microgram DNA). Excretion of Ad5CMV-p53 DNA from bodily secretions was rare. Only one sample of 74 serial urine specimens obtained from 10 patients, and one of 53 rectal swab specimens from six patients were positive. Ad5CMV-p53 DNA was not detected in 15 oral rinse specimens.
Detection of Antibodies to Adenovirus 5
Antitumor Activity There were no objective responses in the 17 patients entered onto this clinical trial. One patient with metastatic and progressive colorectal carcinoma before study entry had durable stable disease and remained on therapy for 10 courses (10 months) at the 3 x 1011 dose level.
Intravenous Ad5CMV-p53 administration represents a novel therapeutic strategy to target and reverse a critical and frequent molecular event in solid tumors—functionally silent p53 gene. Previous clinical studies of Ad5CMV-p53 have examined direct local intratumoral administration.16,18,20,22 However, systemic delivery of this wt-p53 containing adenoviral vector has several potential therapeutic advantages over local injection strategies: systemic intravenous delivery of Ad5CMV-p53 may target the majority of patients with multiple sites of advanced malignant disease; most patients do not have tumors accessible for local injection; and adenoviral vectors, once administered intravenously, can distribute widely in the systemic circulation. Ad5CMV-p53 differs from other adenoviral gene vector approaches administered for the treatment of malignancies. Onyx-015 is a replication-conditional adenoviral construct that has a deleted E1B region thereby permitting viral replication exclusively in defective p53 cells, and whose mechanism of action results in viral replication induced-lysis of tumor cells.23 In contrast, the mechanism of action for Ad5CMV-p53 is the restoration of p53 function in cells accompanied by return of cell cycle control, and/or apoptotic function. A similar adenoviral p53 construct, SCH58500, has been examined extensively using local administration. The starting dose and schedule for this phase I study was equivalent to the starting dose used in several intratumoral injection clinical studies and feasible for multiple administrations.16,18,20,22 In this study, the safety data closely approximated the common related adverse events observed with intratumoral administration including mild or moderate fever, fatigue, nausea, and vomiting, and did not escalate with repetitive administration. Moreover, the results of the current study support the safety of local intratumoral Ad5CMV-p53 administration should unintended cannulation of a blood vessel occur. The one toxicity not anticipated from previous intratumoral studies is the occurrence of transient elevations in PTT, and some patients, elevation of FDP. This finding is suggestive, albeit at a subclinical level, of coagulation cascade activation. This toxicity was without evidence of hemorrhage or thrombosis in those patients and therefore the significance of these abnormal laboratory values is unknown. Nevertheless, an unrelated study utilizing a type 5 adenovirus vector containing cDNA for ornithine transcarbamylase infused intrahepatically, resulted in a constellation of fatal toxicities including elevation in coagulation times and disseminated intravascular coagulation.24 This raised the profile of coagulation toxicities in adenoviral gene therapy studies and based, in part, on these concerns dose escalation above 3 x 1012 vp IV was never attempted. Ad5CMV-p53 was detectable in plasma 14 and 28 days following treatment in the majority of patients treated at 1 x 1012 vp. This suggests that tumor cells may be exposed to Ad5CMV-p53 for several weeks after intravenous treatment. Only a limited number of patients had pharmacologic sampling on course two, and of these patients, a smaller proportion of patients had detectable Ad5CMV-p53 by days 14 and 28. An increase in the titers of adenovirus type-5 immunoglobulin as well as the detection of neutralizing antibodies have been observed with intratumoral injection, and in this study, neutralizing antibodies were detected in five of six patients and strongly in four patients 3 to 4 weeks after first administration.16,20,22 Additional pharmacokinetic studies will be needed to accurately assess the clearance in subsequent courses and determine an optimal treatment window for systemic Ad5CMV-p53 administration. The incremental increase in Ad5CMV-p53 DNA in tumor biopsies distant from the site of administration is an encouraging finding for the development of this agent as a systemic therapy. While direct intratumoral Ad5CMV-p53 injection has been shown to mediate increased tumor apoptosis and tumor regression in some patients, complete tumor penetration has not been demonstrated. In glioblastoma patients receiving direct intratumoral injection, successful p53 transduction within the tumor was confined to a region adjacent to the injection site averaging only 5 mm.22 In this study, evidence of detectable p53 transgene penetration into tumors, accompanied by prolonged systemic circulation of Ad5CMV-p53, supports additional clinical studies to quantify the magnitude of Ad5CMV-p53 penetration following systemic administration and determine if more homogenous transduction may be possible. One potential strategy to optimize tumor cell exposure to the adenovirus and increase transduction would be concurrent local as well as systemic administration of Ad5CMV-p53. Ad5CMV-p53 may have a role reversing aberrant p53-mediated multidrug chemotherapy resistance and sensitizing tumors when coadministered with systemic chemotherapy.25-28 Ad5CMV-p53 in experimental models overcame resistance when combined with chemotherapy, and based on these results, a phase III study is currently comparing the efficacy of intratumoral Ad5CMV-p53 administration with chemotherapy to chemotherapy alone in patients with squamous cell head and neck cancer.11 However, since the measures of clinical efficacy (response and survival) are often dictated by the presence of widely disseminated disease, a full examination of whether Ad5CMV-p53 improves chemotherapy efficacy may require a comparative study of systemic Ad5CMV-p53 with chemotherapy. In this study, the presence of Ad5CMV-p53 DNA within tumor metastasis distant from the intravenous administration site suggests that this hypothesis is testable in clinical studies. In conclusion, Ad5CMV-p53 can be feasibly administered at doses up to 3 x 1012 vp IV daily for 3 days every 28 days to patients with advanced solid tumors with the recommended dose for future disease directed studies is 1 x 1012 vp IV daily for 3 days. The safe, prolonged circulation of the intact vector, and successful transduction of p53 into tumor cells at sites distant from Ad5CMV-p53 IV administration represents an important proof on concept for other gene therapy strategies that utilize type 5 adenoviral vectors that target genetic loss of function. The rational next steps for the development of systemically administered Ad5CMV-p53 will be to perform phase II and pharmacodynamic studies in patients with a known p53 null or mutant genotype (eg, those with the greatest likelihood to benefit) to determine and relate the antitumor activity with the extent of wt-p53 transduction into tumors, and also to examine the combination of Ad5CMV-p53 administered intravenously with cytotoxic agents whose activity is governed by p53 status to determine if restoration of p53 status enhances antitumor effect.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported by Introgen Therapeutics Inc, and NIH Grant No. UO1 CA69853. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Baker SJ, Fearon ER, Nigro JM, et al: Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244:217-221, 1989 2. Isobe M, Emanuel BS, Givol D, et al: Localization of gene for human p53 tumour antigen to band 17p13. Nature 320:84-85, 1986[CrossRef][Medline] 3. Levine AJ, Momand J, Finlay CA: The p53 tumour suppressor gene. Nature 351:453-456, 1991[CrossRef][Medline] 4. Halevy O, Michalovitz D, Oren M: Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250:113-116, 1990 5. Malkin D, Li FP, Strong LC, et al: Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233-1238, 1990 6. Hollstein M, Sidransky D, Vogelstein B, et al: p53 mutations in human cancers. Science 253:49-53, 1991 7. Takahashi T, Nau MM, Chiba I, et al: p53: a frequent target for genetic abnormalities in lung cancer. Science 246:491-494, 1989 8. Sidransky D, Von Eschenbach A, Tsai YC, et al: Identification of p53 gene mutations in bladder cancers and urine samples. Science 252:706-709, 1991 9. Nigro JM, Baker SJ, Preisinger AC, et al: Mutations in the p53 gene occur in diverse human tumour types. Nature 342:705-708, 1989[CrossRef][Medline] 10. Zhang WW, Fang X, Mazur W, et al: High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1:5-13, 1994[Medline] 11. Fujiwara T, Grimm EA, Mukhopadhyay T, et al: Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 54:2287-2291, 1994 12. Shono T, Tofilon PJ, Schaefer TS, et al: Apoptosis induced by adenovirus-mediated p53 gene transfer in human glioma correlates with site-specific phosphorylation. Cancer Res 62:1069-1076, 2002 13. Wang J, Bucana CD, Roth JA, et al: Apoptosis induced in human osteosarcoma cells is one of the mechanisms for the cytocidal effect of Ad5CMV-p53. Cancer Gene Ther 2:9-17, 1995[Medline] 14. Liu TJ, Zhang WW, Taylor DL, et al: Growth suppression of human head and neck cancer cells by the introduction of a wild-type p53 gene via a recombinant adenovirus. Cancer Res 54:3662-3667, 1994 15. Clayman GL, el-Naggar AK, Roth JA, et al: In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res 55:1-6, 1995 16. Nemunaitis J, Swisher SG, Timmons T, et al: Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. J Clin Oncol 18:609-622, 2000 17. Clayman GL, el-Naggar AK, Lippman SM, et al: Adenovirus-mediated p53 gene transfer in patients with advanced recurrent head and neck squamous cell carcinoma. J Clin Oncol 16:2221-2232, 1998[Abstract] 18. Swisher SG, Roth JA, Nemunaitis J, et al: Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer Inst 91:763-771, 1999 19. Swisher SG, Roth JA, Komaki R, et al: Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clin Cancer Res 9:93-101, 2003 20. Wolf JK, Bodurka DC, Gano JB, et al: A phase I study of Adp53 (INGN 201; ADVEXIN) for patients with platinum- and paclitaxel-resistant epithelial ovarian cancer. Gynecol Oncol 94:442-448, 2004[CrossRef][Medline] 21. Saulnier P, Vidaud M, Gautier E, et al: Development and validation of a real-time PCR assay for the detection and quantitation of p53 recombinant adenovirus in clinical samples from patients treated with Ad5CMV-p53 (INGN 201). J Virol Meth 114:55-64, 2003[CrossRef][Medline] 22. Lang FF, Bruner JM, Fuller GN, et al: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: Biological and clinical results. J Clin Oncol 21:2508-2518, 2003 23. Nemunaitis J, Cunningham C, Buchanan A, et al: Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: Safety, feasibility and biological activity. Gene Ther 8:746-759, 2001[CrossRef][Medline] 24. Raper SE, Chirmule N, Lee FS, et al: Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genetics Metab 80:148, 2003[CrossRef][Medline] 25. Rusch V, Klimstra D, Venkatraman E, et al: Aberrant p53 expression predicts clinical resistance to cisplatin-based chemotherapy in locally advanced non-small cell lung cancer. Cancer Res 55:5038-5042, 1995 26. Anthoney DA, McIlwrath AJ, Gallagher WM, et al: Microsatellite instability, apoptosis, and loss of p53 function in drug-resistant tumor cells. Cancer Res 56:1374-1381, 1996 27. Perego P, Giarola M, Righetti SC, et al: Association between cisplatin resistance and mutation of p53 gene and reduced bax expression in ovarian carcinoma cell systems. Cancer Res 56:556-562, 1996 28. Berns EM, Foekens JA, Vossen R, et al: Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer. Cancer Res 60:2155-2162, 2000 Submitted July 29, 2005; accepted February 17, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
