Advertisement
help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chabner, B. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chabner, B. A.
The Oncologist, Vol. 7, Suppl 3, 34-41, August 2002
© 2002 AlphaMed Press

Cytotoxic Agents in the Era of Molecular Targets and Genomics

Bruce A. Chabner

Massachusetts General Hospital, Boston, Massachusetts, USA

Correspondence: Bruce Chabner, M.D., Hematology/Oncology Associates, 100 Blossom Street, Cox 640, Boston, Massachusetts 02114-2617, USA. Telephone: 617-724-3200; Fax: 617-724-3166; e-mail: bchabner{at}partners.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Identify single nucleotide polymorphisms.
  2. Explain how they could influence drug response and toxicity in cancer patients.
  3. Explain how the DNA repair capability of tumor cells affects their response to ET-743 and other cancer drugs.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
Cancer treatment is evolving due to the development of molecularly targeted agents and the utilization of pharmacogenomics and pharmacogenetics to identify patients who are at an increased risk for toxicity or may be uniquely responsive to cytotoxic therapies. By identifying polymorphisms in the human genome that confer changes in the ability to metabolize or activate cancer agents, a more patient-specific treatment approach can be initiated. Molecularly targeted therapies such as PS-341, flavopiridol, Iressa, and anti-vascular endothelial growth factor antibodies may help to overcome resistance to cytotoxic therapies by lowering the apoptotic threshold and increasing cytotoxicity. Using molecularly targeted agents in combination with traditional cytotoxic agents may increase the percentage of patients who achieve disease stabilization and prolonged survival. With the development of genetic tools and genotyping of tumor and patient prior to initiating treatment, antitumor efficacy may be increased with a substantial reduction in toxicity.

Key Words. Pharmacogenomics • Pharmacogenetics • Polymorphism • Molecular targeting


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
Basic cancer treatment is changing due to advances in molecular targeting and the utilization of pharmacogenomics and pharmacogenetics to identify patients who are at increased risk for toxicity and select those more likely to respond to specific chemotherapeutic agents. The future emphasis of cancer pharmacology is to identify a new class of molecules that block critical targets, particularly those that inhibit signal transduction pathways, and to develop agents with favorable pharmacokinetics (long terminal half-life), oral bioavailability, and acceptable toxicity profiles.

A number of new approaches are being used in clinical trials of molecularly targeted agents to evaluate response rates, prevent toxicity, and identify potentially active drugs. Screening tumors prior to chemotherapy treatment may help to identify patients who would benefit from combination therapy with traditional cytotoxic agents and molecularly targeted agents. Molecular pathology will help to identify whether specific molecular entities are present or overexpressed in tumors. With this information, investigators can select the appropriate agent to limit the risk of unnecessary toxicity and increase the chance of response. The use of in vivo imaging to monitor drug effect on target and surrogate serum markers for response will help to assess the potential of new drugs. Long-term end-points such as survival or time to progression are needed in phase III trials of cytotoxic drugs and molecularly targeted agents to fully evaluate response and confirm the value of new agents.

This article will discuss the use of molecular biology to identify patients at increased risk for toxicity and select those potentially responsive to particular chemotherapeutic agents; the rationale for combining traditional cytotoxic therapies with molecularly targeted agents; and the development of ecteinascidin-743 (ET-743), a novel, molecularly targeted, natural product that is currently under early clinical development for the treatment of soft tissue sarcoma, bone sarcoma, and breast cancer.


   THE USE OF MOLECULAR BIOLOGY TO IDENTIFY PATIENTS AT RISK FOR TOXICITY
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
Polymorphisms in the human genome confer changes in the ability to metabolize or activate cancer agents. Over a million single nucleotide polymorphisms have been identified and regularly occur in the human population. Information derived from identifying specific polymorphisms will help to design effective chemotherapeutic regimens while reducing the risk of treatment-related toxicities. One example of a polymorphism affecting drug toxicity occurs in the 6-mecaptopurine (6-MP) activation and degradation pathways (Fig. 1Go). Thiopurine S-methyltransferase (TPMT) converts the basic 6-MP molecule to a methylated derivative, which has much less activity than the parent compound. In the absence of TPMT activity, more 6-MP-related toxicities occur, including myelosuppression, due to the excessive accumulation of thioguanine nucleotides in hematopoietic tissues [1–3]. TPMT is found in peripheral red blood cells. By measuring TPMT activity in these cells, it is possible to detect patients with lower than normal enzyme activity. Approximately 11% of patients with leukemia have at least one mutant allele and 0.3% are homozygous for mutant alleles (Table 1Go) [4–6]. Patients homozygous for mutant alleles with no TPMT activity have the greatest potential for toxicity. By identifying patients with TPMT deficiency prior to treatment, a less toxic dose of 6-MP can be chosen to limit the potential for severe myelosuppression.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 1. Thiopurine metabolism: 6-MP activation and degradation pathways. XO = xanthine oxidase; TPMT = thiopurine S-methyltransferase; HPRT = hypoxanthine phosphoribosyl transferase; GMP = guanosine monophosphate.

 

View this table:
[in this window]
[in a new window]
  		Table 1. TPMT genotype and enzyme activity levels in patients with leukemia when measured in peripheral red blood cells [5–7]
 
A second example of a polymorphism influencing cancer drug toxicity is the occurrence of dihydropyrimidine dehydrogenase (DPD) deficiency in patients receiving 5-fluorouracil (5-FU). DPD is the initial enzyme and rate-limiting step in the degradation pathway of 5-FU (Fig. 2Go). Increased toxicity to 5-FU, including death, has been observed in patients with decreased DPD activity [7–9]. Among a mixed population of 103 cancer patients who experienced unexpected 5-FU toxicities, 12 patients (12%) were identified as having profoundly deficient DPD enzyme activity and 32 patients (31%) were identified as having partial DPD enzyme activity [10]. In a study by van Kuilenburg et al., 55% of the patients with DPD deficiencies experienced grade IV neutropenia, as opposed to 13% of the patients with normal DPD activity (p = .01) [8]. The significant 5-FU-associated toxicities, in some cases leading to death, in patients with DPD deficiency warrant development of standardized methods for genetic screening for the presence of this mutation before the administration of 5-FU.



View larger version (7K):
[in this window]
[in a new window]
  		Figure 2. Key enzymes in 5-FU response. TP = thymidine phosphorylase; DPD = dihydropyrimidine dehydrogenase; TK = thymidine kinase; TS = thymidylate synthase.

 
The level of tumor DPD expression may also be useful to predict response to 5-FU. The 5-FU activation and degradation pathways are shown in Figure 2Go. The base 5-FU is activated to the nucleoside 5-FUdR by the enzyme thymidine phosphorylase (TP), but this is a reversible reaction, and may in fact degrade the 5-FUdR formed by alternative pathways. 5-FUdR is further activated by phosphorylation and the active metabolite 5-FdUMP is the tight binding inhibitor of thymidylate synthase (TS). Increases in the activity of any of these enzymes, DPD, TP, or TS, can lead to drug resistance. In 33 patients with colon cancer who were treated with 5-FU and leucovorin, expression of DPD, TP, and TS in tumors was correlated with response to 5-FU [11]. Among 22 patients with high levels of DPD, TS, or TP, no patients responded [12]. A 50% partial response rate was observed in tumors with low levels of DPD (<2.5 x 10–3 units/mg protein), whereas no responses were observed in patients with elevated DPD (>2.5 x 10–3 units/mg protein) [12]. Hence, measuring gene expression in the tumor has the potential to identify tumors that are uniquely susceptible to 5-FU, and may help to exclude patients unlikely to respond.

Another polymorphism that was recently discovered in the folate pathway may provide insight regarding the probability of response to methotrexate therapy. Investigators in Japan discovered a C to T transition in the 3' untranslated region of dihydrofolate reductase (DHFR); this change is found in 16% of patients with acute lymphocytic leukemia and leads to overexpression of the enzyme [11]. In blast cells with the wild-type C and a T allele, or those that were homozygous for the T mutation or polymorphism, there was a 2- to 10-fold increase in DHFR expression. Increases in DHFR expression are associated with a decreased response to methotrexate [13].


   THE USE OF NEW MOLECULAR THERAPIES IN COMBINATION WITH TRADITIONAL CYTOTOXIC AGENTS
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
Single drug therapy is unlikely to be curative in cancer. Because cytotoxic agents have the ability to reduce tumor burden, these agents will continue to be important in cancer treatment. Combination regimens of cytotoxic drugs and molecularly targeted agents may help to improve response rates and address drug resistance by lowering the apoptotic threshold or influencing the cell response to DNA damage.

PS-341, a dipeptide boronic acid analogue and an inhibitor of proteasome function (it inhibits the chymotryptic activity of the 20S proteasome), may reverse drug resistance to conventional cytotoxic anticancer therapies by blocking the response of tumor cells to DNA damage. PS-341 induces tumor cell apoptosis [14]. It is a potent inhibitor of the damage response mediated by nuclear factor-{kappa}B (NF-{kappa}B) [15], a transcription factor that has been implicated in promoting tumor cell survival [16–18]. In a study by Hideshima et al., PS-341 inhibited tumor necrosis factor-alpha–induced elevation of NF-{kappa}B in multiple myeloma cells by stabilizing the NF-{kappa}B inhibitory protein I{kappa}B-a [19]. PS-341 inhibited the growth of known chemoresistant cell lines, overcoming resistance to doxorubicin, mitoxantrone, melphalan, and dexamethasone [19]. PS-341 also has shown synergistic activity in preclinical studies with irinotecan by suppressing the damage response and lowering the apoptotic threshold [20, 21].

Another molecularly targeted agent, flavopiridol, is a potent cyclin-dependent kinase (CDK) inhibitor and an analog of a naturally occurring flavonoid isolated from the stem bark of Dysoxylum binectariferum [22]. Flavopiridol appears to inhibit transcription globally, resulting in a gene expression profile resembling other transcription inhibitors such as actinomycin D [23]. Flavopiridol has been shown to increase sensitivity to gemcitabine and enhance the induction of apoptosis in human pancreatic, gastric, and colon cancer cell lines [24]. The apoptotic induction appears to be sequence-dependent, with gemcitabine followed by flavopiridol achieving the greatest increase in apoptosis [24].

In a phase II trial, 20 patients with previously untreated stage IV non-small cell lung cancer (NSCLC) were treated with a 72-h continuous infusion of flavopiridol 50 mg/m2 every 14 days [22]. Although no objective responses were observed, three patients (15%) experienced minor responses that were sustained for at least 4 weeks. Ten patients (50%) had stable disease when evaluated after 8 weeks, and the median overall survival was 7.5 months. Flavopiridol was well tolerated; the most common toxicities were grade 1/2 diarrhea (11 patients, 55%), grade 2/3 fatigue (8 patients, 40%), and grade 1 nausea (10 patients, 50%) [22].

Combination therapy with flavopiridol and trastuzumab is a rational regimen due to the complementary mechanisms of action of these therapies. Trastuzumab is an inhibitor of the HER2/neu signaling pathway and mediates its effects by blocking downstream signaling through the pRb pathway. By inhibiting CDK-4, a key enzyme in the pRb pathway, flavopiridol contributes further blockade at one of the activated targets of HER2/neu signaling. Thus, the two molecules should work in sequence on a common pathway [25].

Epidermal growth factor receptor (EGFR) activation increases the threshold for apoptosis for cytotoxic drugs and can increase the potential for drug resistance [26]. ZD1839 (Iressa), an oral selective, reversible inhibitor of EGFR tyrosine kinase [26–29], has the potential to reset the apoptotic threshold for cytotoxic drugs by blocking signal transduction pathways implicated in cancer growth [30–33]. In preclinical studies, enhancement of cell growth inhibition and increased antitumor activity was observed when Iressa was combined with traditional chemotherapeutic agents such as paclitaxel, docetaxel, carboplatin, and cisplatin [26, 34–36]. Iressa has demonstrated activity in a variety of experimental testing with various cancer types including colorectal, NSCLC, ovarian, head and neck, renal, and hormone-resistant prostate tumors [31, 32]. In phase I trials, Iressa was well tolerated and showed early evidence of efficacy in patients with solid tumors refractory to standard chemotherapeutic agents [27, 28, 33].

The preclinical finding of enhanced antitumor activity of chemotherapy with the addition of Iressa has lead to combination therapy trials. Among 25 patients with advanced NSCLC who were treated with two courses of carboplatin and paclitaxel in combination with 2 weeks of Iressa, 7 patients (28%) achieved a partial response, 10 patients (40%) achieved disease stabilization, 3 patients (12%) had progressive disease, and 5 patients (20%) had no response [34]. Because tumors with HER2/neu overexpression are particularly sensitive to Iressa [35], Moasser et al. investigated the efficacy of Iressa in combination with trastuzumab and found additive growth inhibition when the two agents were combined. Phase III trials of Iressa in combination with carboplatin/paclitaxel and cisplatin/gemcitabine as first-line treatment in nonoperable stage III/IV NSCLC are currently under way.


   ET-743
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
Combination Therapy with ET-743
 Conclusions
 References
 
The potential for molecular profiling of tumors in the selection of chemotherapy is illustrated by the development of a new natural product ET-743, isolated from the Caribbean marine tunicate Ecteinascidia turbinata. This potent antitumor agent has activity in a variety of in vitro and in vivo systems [36–38]. ET-743 targets DNA by binding in the minor groove in GC-rich sequences and alkylating the 2-amino group of guanine [39]. The downstream effects of alkylation are still unclear. ET-743 potentiates the cytotoxicity of a number of other drugs, including cisplatin [40–42]. Alkylation in the minor groove produces bending of DNA toward the major groove [43], which is then recognized by the nucleotide excision repair (NER) pathway [44]. These DNA breaks lead to cell death and apoptosis. ET-743 has demonstrated cytotoxic activity in many cancer cell lines and xenografts, including melanoma [39, 45], ovarian cancer [39–41], soft tissue sarcoma [39, 46], breast cancer [39], and NSCLC tumors [39, 45].

Phase I trials of ET-743 conducted in the U.S. and Europe have investigated multiple dosing regimens, including a 1-hour daily infusion for 5 days or a 3-, 24-, or 72-hour infusion administered every 3 weeks [47–50]. The dose-limiting toxicities observed in these trials were primarily neutropenia, thrombocytopenia, and asthenia/fatigue. Increases in alanine amino-transferase and aspartate aminotransferase were reversible and not dose limiting [47–50]. Toxicity of ET-743 is schedule-dependent; increasing the duration of infusion from 3 or 24 hours to 72 hours results in less myelosuppression and comparable or greater hepatotoxicity [47]. Its activity seems promising in soft tissue sarcoma, a notoriously drug-resistant disease.

Twenty-nine patients with advanced soft tissue sarcoma and bone sarcoma who were previously treated with anthracyclines and alkylators received ET-743 in a phase I trial [50]. Patients received ET-743 1,200 µg/m2 (six patients), 1,500 µg/m2 (22 patients), or 1800 µg/m2 (one patient) administered as a 24-hour infusion every 3 weeks. Four partial responses (14%), two minor responses (7%), and 10 patients (34%) with disease stabilization were observed. The median duration of response (including minor responses) was 10.5 months (range, 2.8 to 15 months) and the mean duration of disease stabilization was 5.2 months [50]. The finding that ET-743 has activity in patients with advanced, previously treated soft tissue sarcoma is significant given the general lack of chemotherapeutic agents in patients with this tumor type.

A phase I dose-finding study of ET-743 administered as a 24-hour infusion every 3 weeks has provided valuable pharmacokinetic information. The maximum-tolerated dose was 1,800 µg/m2 and the recommended dose for phase II trials was 1,500 µg/m2 for patients with normal baseline hepatobiliary function tests and performance status <=1 [48]. Pharmacokinetic analysis revealed a linear relationship between increased dose and increased area under the curve (AUC) and Cmax. The grade of neutropenia and thrombocytopenia was correlated with the AUC, but there were no correlations between the grades of nausea, vomiting, or fatigue with either AUC or Cmax [48].

Phase II studies of ET-743 in previously treated patients with soft tissue sarcomas have recently been completed. In the largest of these trials, at the Dana Farber/Harvard Cancer Center, the response rate was 11%. Response rates were higher among patients who had received one prior line of treatment compared with patients who had received two prior treatment courses (Table 2Go) [51]. Although the overall response rates in these trials are not impressive, about 40% of patients treated with ET-743 had stable disease for 2 months or more [52]. The duration of time to progression with ET-743 is considerably greater than in historical control trials utilizing ifosfamide or dacarbazine. For example, in the European Organization for Research on the Treatment of Cancer studies, 16% of patients treated with other second-line therapy had progression-free survival at 6 months compared with 25% to 28% of patients treated with ET-743 in the same setting.


View this table:
[in this window]
[in a new window]
  		Table 2. ET-743 in soft tissue sarcomas: response to treatment by protocol
 
In ongoing trials in breast cancer patients, ET-743 has shown a partial response rate of approximately 13% [53]. Among 16 breast cancer patients treated with ET-743, two partial responses lasting >=2 months were noted and six patients achieved either a minor response or stable disease. In an ongoing phase II study among 16 evaluable patients with ovarian cancer relapsing from a resistance to taxane and platinum therapy, ET-743 administered as a 3-hour infusion resulted in one complete response (6%), one partial response (6%), and six patients (38%) with stable disease lasting over 3 months [54].


   COMBINATION THERAPY WITH ET-743
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
Conclusions
 References
 
ET-743 cytotoxicity is mediated by the transcription-coupled NER pathway [44, 55]. In a study by Takebayashi et al, cells deficient in NER genes (XPF, XPG, XPA, and XPD) were resistant to ET-743 activity [44]. NER-deficient cells became sensitive to ET-743 when the mutant repair protein, any one of the several potential mutations, was restored by transfection. Thus, an intact transcription-coupled NER pathway is essential to ET-743 activity. ET-743 was more cytotoxic in mismatch-repair-deficient cells, suggesting that mismatch-repair deficiency does not contribute to ET-743 resistance [44].

The finding that ET-743 cytotoxicity is mediated by the NER pathway raises some interesting possibilities for combination chemotherapy, particularly for cisplatin. In contrast to ET-743, cisplatin resistance has opposite relationships to repair; cisplatin resistance is conferred by mismatch-repair deficiency [56] and by NER overexpression [57]. Because mismatch-repair-deficient cells and NER overexpressing cells are sensitive to ET-743 [44, 55], combination therapy with cisplatin is logical. Thus it will be important to determine the relationship of response and NER pathway expression in future clinical trials.

In a study by Takahashi et al., concurrent exposure of ET-743 and doxorubicin resulted in synergism in two soft tissue sarcoma cell lines [58]. Sequential exposure of ET-743 for 24 hours, and doxorubicin also showed a synergistic toxic effect and proved more effective than concomitant exposure [58].

The next step for ET-743 will be the completion of phase I trials of the weekly 1-hour infusion. It appears that about one-third of the dose tolerated in the 3- and 24-hour infusions will be tolerated on a weekly basis, but with better patient tolerance. Combination trials with platinums and anthracyclines, and broader phase II trials in patients with breast, ovarian, and prostate carcinomas are needed to further establish the efficacy and tolerability of ET-743.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
References
 
Tumor genetics and pharmacogenomics will help to select tumors that will be responsive to cytotoxic agents and to reduce the risk of chemotherapy-associated toxicities. Combinations of cytotoxics with molecularly targeted agents may help to overcome chemotherapy resistance by lowering the apoptotic threshold and influencing the damage response. A better characterization of both the host and tumor in terms of genetic profile of susceptibility to drug toxicity and susceptibility to drug response is needed for the rational use of chemotherapy. With the appropriate development of genetic tools and the genotyping of tumor and patient prior to initiating treatment, antitumor efficacy may increase with a substantial reduction in toxicity.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 
Dr. Chabner is a consultant, advisor, or equity holder of Pharmamar, Kosan, Cephalon, Eli Lilly, Johnson and Johnson, Pfizer, and Vion.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 The Use of Molecular...
 The Use of New...
 ET-743
 Combination Therapy with ET-743
 Conclusions
 References
 

  1. Evans WE, Hon YY, Bomgaars L et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001;19:2293–2301.[Abstract/Free Full Text]
  2. Lennard L, Van Loon JA, Lilleyman JS et al. Thiopurine pharmacogenetics in leukemia: correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations. Clin Pharmacol Ther 1987;41:18–25.[Medline]
  3. Relling MV, Hancock ML, Rivera GK et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999;91:2001–2008.[Abstract/Free Full Text]
  4. Lennard L. Therapeutic drug monitoring of cytotoxic drugs. Br J Clin Pharmacol 2001;52:75S–87S.
  5. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32:651–662.[Medline]
  6. Vuchetich JP, Weinshilboum RM, Price RA. Segregation analysis of human red blood cell thiopurine methyltransferase activity. Genet Epidemiol 1995;12:1–11.[CrossRef][Medline]
  7. van Kuilenburg ABP, Muller EW, Haasjes J et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 2001;7:1149–1153.[Abstract/Free Full Text]
  8. van Kuilenburg ABP, Haasjes J, Richel DJ et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000;6:4705–4712.[Abstract/Free Full Text]
  9. Johnson MR, Hageboutros A, Wang K et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999;5:2006–2011.[Abstract/Free Full Text]
  10. Johnson MR, Diasio RB. Importance of dihydropyrimidine dehydrogenase (DPD) deficiency in patients exhibiting toxicity following treatment with 5-fluorouracil. Adv Enzyme Regul 2001;41:151–157.[CrossRef][Medline]
  11. Goto Y, Yue L, Yokoi A et al. A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression. Clin Cancer Res 2001;7:1952–1956.[Abstract/Free Full Text]
  12. Salonga D, Danenberg KD, Johnson M et al. Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000;6:1322–1327.[Abstract/Free Full Text]
  13. Saikawa Y, Knight CB, Saikawa T et al. Decreased expression of the human folate receptor mediates transport-defective methotrexate resistance in KB cells. J Biol Chem 1993;268:5293–5301.[Abstract/Free Full Text]
  14. Frankel A, Man S, Elliott P et al. Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor PS-341. Clin Cancer Res 2000;6:3719–3728.[Abstract/Free Full Text]
  15. Sunwoo JB, Chen Z, Dong G et al. Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kB, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 2001;7:1419–1428.[Abstract/Free Full Text]
  16. van Antwerp DJ, Marin SJ, Kafri T et al. Suppression of TNF-{alpha}-induced apoptosis by NF-kB. Science 1996;274:787–789.[Abstract/Free Full Text]
  17. Wang C-Y, Mayo MW, Baldwin Jr AS et al. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kB. Science 1996;274:784–787.[Abstract/Free Full Text]
  18. Beg AA, Baltimore D. An essential role for NF-kB in preventing TNF-{alpha}-induced cell death. Science 1996;274:782–784.[Abstract/Free Full Text]
  19. Hideshima T, Richardson P, Chauhan D et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071–3076.[Abstract/Free Full Text]
  20. Shah SA, Potter MW, McDade TP et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem 2001;82:110–122.[CrossRef][Medline]
  21. Cusack Jr JC, Liu R, Houston M et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kB inhibition. Cancer Res 2001;61:3535–3540.[Abstract/Free Full Text]
  22. Shapiro GI, Supko JG, Patterson A et al. A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer. Clin Cancer Res 2001;7:1590–1599.[Abstract/Free Full Text]
  23. Lam LT, Pickeral OK, Peng AC et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2001;2:1–11.
  24. Jung CP, Motwani MV, Schwartz GK. Flavopiridol increases sensitization to gemcitabine in human gastrointestinal cancer cell lines and correlates with down-regulation of ribonucleotide reductase M2 subunit. Clin Cancer Res 2001;7:2527–2536.[Abstract/Free Full Text]
  25. Wu K, Wang C, Lee RJ et al. Flavopiridol synergizes with e-erb-B-2 inactivation to inhibit multiple signal transduction pathways involved in breast cancer cellular proliferation. Proc Am Assoc Cancer Res 2001;42:86.
  26. Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958–2970.[Abstract/Free Full Text]
  27. Ferry D, Hammond L, Ranson M et al. Intermittent oral Zd1839 (Iressa), a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), shows evidence of good tolerability and activity: final results from a phase I study. Proc Am Soc Clin Oncol 2000;19:3a.
  28. Baselga J, Herbst R, LoRusso P et al. Continuous administration of ZD1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients with five selected tumor types: evidence of activity and good tolerability. Proc Am Soc Clin Oncol 2000;19:177a.
  29. Wells A. Molecules in focus EGFR receptor. Int J Biochem Cell Biol 1999;31:637–643.[CrossRef][Medline]
  30. Perry JE, Grossman ME, Tindall DJ. Epidermal growth factor induces cyclin D1 in a human prostate cancer cell line. Prostate 1998;35:117–124.[CrossRef][Medline]
  31. Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily. Role as anticancer agents. Drugs 2000;59:753–767.[CrossRef][Medline]
  32. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999;82:241–250.[CrossRef][Medline]
  33. Kris MG, Herbst R, Rischin D et al. Objective regressions in non-small cell lung cancer patients treated in phase I trials of oral ZD1839 (‘Iressa’), a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor (EGFR). Lung Cancer 2000;29(suppl 1):72.
  34. Miller VA, Johnson D, Heelan RT et al. A pilot trial demonstrates the safety of ZD1839 (‘Iressa’), an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with carboplatin (C) and paclitaxel (P) in previously untreated advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001;20:326a.
  35. Moasser MM, Basso A, Averbuch SD et al. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 2001;61: 7184–7188.[Abstract/Free Full Text]
  36. Izbicka E, Lawrence R, Raymond E et al. In vitro antitumor activity of the novel marine agent, ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann Oncol 1998;9:981–987.[Abstract/Free Full Text]
  37. Valoti G, Nicoletti MI, Pellegrino A et al. Ecteinascidin-743, a new marine natural product with potent antitumor activity in human ovarian carcinoma xenografts. Clin Cancer Res 1998;4:1977–1983.[Abstract]
  38. Ghielmini M, Colli E, Erba E et al. In vitro schedule-dependency of myelotoxicity and cytotoxicity of ecteinascidin 743 (ET-743). Ann Oncol 1998;9:989–993.[Abstract/Free Full Text]
  39. Pommier Y, Kohlhagen G, Bailly C et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 1996;35:13303–13309.[CrossRef][Medline]
  40. Ciardiello F, Caputo R, Bianco R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000;6:2053–2063.[Abstract/Free Full Text]
  41. Sirotnak FM, Zakowsky MF, Miller VA et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000;6:4885–4892.[Abstract/Free Full Text]
  42. Ohmori T, Ao Y, Nishio K et al. Low dose cisplatin can modulate the sensitivity of human non-small cell lung carcinoma cells to EGFR tyrosine kinase inhibitor (ZD1839; ‘Iressa’) in vivo. Proc Am Assoc Cancer Res 2000;41:482.
  43. Zewail-Foote M, Hurley LH. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J Med Chem 1999;42:2493–2497.[CrossRef][Medline]
  44. Takebayashi Y, Pourquier P, Zimonjic DB et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med 2001;7:961–966.[CrossRef][Medline]
  45. Hendriks HR, Fiebig HH, Giavazzi R et al. High antitumor activity of ET-743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann Oncol 1999;10:1233–1240.[Abstract/Free Full Text]
  46. Li WW, Takahashi N, Jhanwar S et al. Sensitivity of soft tissue sarcoma cell lines to chemotherapeutic agents: identification of ecteinascidin-743 as a potent cytotoxic agent. Clin Cancer Res 2001;7:2908–2911.[Abstract/Free Full Text]
  47. Ryan DP, Supko JG, Eder JP et al. Phase I and pharmacokinetic study of ecteinascidin 743 administered as a 72-hour continuous intravenous infusion in patients with solid malignancies. Clin Cancer Res 2001;7:231–242.[Abstract/Free Full Text]
  48. Taamma A, Misset JL, Riofrio M et al. Phase I and pharmacokinetic study of ecteinascidin-743, a new marine compound, administered as a 24-hour continuous infusion in patients with solid tumors. J Clin Oncol 2001;19:1256–1265.[Abstract/Free Full Text]
  49. van Kesteren C, Cvitkovic E, Taamma A et al. Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study. Clin Cancer Res 2000;6:4725–4732.[Abstract/Free Full Text]
  50. Delaloge S, Yovine A, Taamma A et al. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 2001;19:1248–1255.[Abstract/Free Full Text]
  51. Demetri GD, Manola J, Harmon D et al. Ecteinascidin-743 (ET-743) induces durable responses and promising 1-year survival rates in soft tissue sarcomas (STS): final results of phase II and pharmacokinetic studies in the U.S.A. Proc Am Soc Clin Oncol 2001;20:352a.
  52. LeCesne A, Blay J, Judson I et al. ET-743 is an active drug in adult soft-tissue sarcoma (STS): a STBSG-EORTC phase II trial. Proc Am Soc Clin Oncol 2001;20:1407.
  53. Zelek L, Yavine A, Brain E et al. Ecteinascidin-743 (ET-743) in taxane (T)/anthracycline (A) pretreated advanced metastatic breast cancer (A/MBC) patients (Pts); preliminary results with the 24 hour continuous infusion (ci) q 3 week schedule. Proc Am Soc Clin Oncol 2000;19:592.
  54. Curiglianó G, Bauer J, Capri G et al. Ecteinascidin 743 (ET-743) in ovarian cancer : activity in xenografts and preliminary results of an ongoing study in patients failing platinum taxanes. Clin Cancer Res 2001;7 (suppl):380.
  55. Damia G, Silvestri S, Carrassa L et al. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer 2001;92:583–588.[CrossRef][Medline]
  56. Abei S, Fink D, Gordon R et al. Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells. Clin Cancer Res 1997;3:1763–1767.[Abstract]
  57. Ferry KV, Hamilton TC, Johnson SW. Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells. Role of ercc1-xpf. Biochem Pharmacol 2000;60:1305–1313.[CrossRef][Medline]
  58. Takahashi N, Li WW, Banerjee D et al. Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin Cancer Res 2001;7:3251–3257.[Abstract/Free Full Text]
Received April 30, 2002; accepted for publication May 17, 2002.




This article has been cited by other articles:


Home page
 CA Cancer J ClinHome page
G. Y. Yang, T. D. Wagner, M. Fuss, and C. R. Thomas Jr.
Multimodality Approaches for Pancreatic Cancer
CA Cancer J Clin, November 1, 2005; 55(6): 352 - 367.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. B. Brunner, K. A. Cengel, S. M. Hahn, J. Wu, D. L. Fraker, W. G. McKenna, and E. J. Bernhard
Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras
Cancer Res., September 15, 2005; 65(18): 8433 - 8441.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
Y. J. Chua and D. Cunningham
Adjuvant Treatment for Resectable Pancreatic Cancer
J. Clin. Oncol., July 10, 2005; 23(20): 4532 - 4537.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
T. G. Roberts Jr, T. J. Lynch Jr, and B. A. Chabner
The Phase III Trial in the Era of Targeted Therapy: Unraveling the "Go or No Go" Decision
J. Clin. Oncol., October 1, 2003; 21(19): 3683 - 3695.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Roentgenol.Home page
E. P. Tamm, P. M. Silverman, C. Charnsangavej, and D. B. Evans
Diagnosis, Staging, and Surveillance of Pancreatic Cancer
Am. J. Roentgenol., May 1, 2003; 180(5): 1311 - 1323.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chabner, B. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chabner, B. A.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS