|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3130-3136 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9298 Topotecan Is Active Against Wilms’ Tumor: Results of a Multi-Institutional Phase II Study
From the St Jude Children's Research Hospital, Memphis, TN; Texas Children's Hospital, Houston, TX; Dana-Farber Cancer Institute, Boston, MA; Children's Healthcare of Atlanta, Atlanta, GA; Alberta Children's Hospital, Calgary, Alberta; and the Hospital for Sick Children, Toronto, Ontario, Canada Address reprint requests to Jeffrey S. Dome, MD, Division of Oncology, Center for Cancer and Blood Disorders, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010-2979; e-mail: jdome{at}cnmc.org
Purpose: A phase II study was conducted to evaluate the activity and safety of topotecan in pediatric patients with recurrent Wilms' tumor. Patients and Methods: Patients with favorable histology Wilms' tumor (FHWT) and recurrence after at least one salvage chemotherapy regimen or with anaplastic histology Wilms' tumor (AHWT) in first or subsequent recurrence were eligible. Patients were stratified according to histology, with statistical considerations based on the FHWT stratum. Topotecan was administered intravenously over 30 minutes for 5 days on 2 consecutive weeks. Treatment dosages were adjusted to achieve a target area under the curve (AUC) of 80 ± 10 ng/mL*h. Tumor responses were measured after two cycles of treatment. Results: Thirty-seven patients (26 patients with FHWT) were enrolled and received a total of 94 cycles of topotecan (range, one to six cycles). The median topotecan dosage required to achieve the target AUC was 1.8 mg/m2 (range, 0.7 to 3.2 mg/m2). Of 25 assessable patients with FHWT, 12 had partial response (PR), six had stable disease (SD), and seven had progressive disease (PD), for an overall response rate of 48% (95% CI, 27.8% to 68.7%). Of 11 assessable patients with AHWT, two had PR, one had SD, and eight had PD. The main toxicities were grade 3 and 4 neutropenia (median duration, 13 days) and thrombocytopenia (median duration, 7.5 days). Conclusion: Topotecan administered on a protracted schedule is active against recurrent FHWT. Inclusion of topotecan in front-line clinical trials for patients with recurrent Wilms' tumor should be considered.
The treatment of Wilms' tumor is one of the great success stories in oncology, but certain subgroups of patients do not fare well, including those with anaplastic histology, bilateral disease, and recurrent disease.1-3 For patients with recurrent Wilms' tumor, relapse-free survival (RFS) has improved significantly since the 1980s with the use of intensive chemotherapy or high-dose therapy with autologous stem-cell rescue.1,4-9 Despite the use of modern treatment regimens, 4-year RFS rate for patients treated initially with vincristine/dactinomycin is approximately 70%, and 4-year RFS rate for patients treated initially with vincristine/dactinomycin/doxorubicin is approximately 40%.7,10 Patients with recurrent anaplastic Wilms' tumor have particularly poor salvage rates; fewer than 15% of such patients achieve durable survival.2 Novel agents and treatment strategies are needed for patients with high-risk or recurrent Wilms' tumor. Topotecan is a camptothecin analog that interacts with topoisomerase I and causes DNA double-strand breaks in an S phase–dependent manner.11 Topotecan has previously shown activity against various pediatric solid tumors including neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and medulloblastoma.12-16 Xenograft studies have suggested that the activity of topotecan is schedule dependent, producing a higher frequency of responses when administered on a protracted schedule of administration rather than an intermittent high-dose regimen.17 In Wilms' tumor xenograft models, six of eight favorable histology models and one anaplastic histology model responded to topotecan at systemic exposures that are achievable in patients.18 On the basis of the preclinical data and promising results of phase I studies,19 we conducted a phase II study to estimate the response rate of topotecan in patients with recurrent Wilms' tumor.
Patient Selection The study of topotecan in children with recurrent Wilms' tumor was a multi-institutional phase II trial including St Jude Children's Research Hospital, Dana-Farber Cancer Institute, Alberta Children's Hospital, Texas Children's Hospital, Children's Hospital of Atlanta, and the Hospital for Sick Children in Toronto. Patients were eligible if they had recurrent or progressive favorable histology Wilms' tumor (FHWT) after primary treatment and at least one standard salvage treatment regimen or if they had recurrent or progressive anaplastic histology Wilms' tumor (AHWT) after primary treatment. Other eligibility requirements included age  21 years, absolute neutrophil count (ANC)  1,000/µL and platelet count 100,000/µL unsupported by transfusion, a serum bilirubin less than 1.5x the upper limit of normal for age, and an Eastern Cooperative Oncology Group performance status20 of 0 to 2. The protocol was approved by the institutional review boards of all participating institutions, and all patients, parents, or guardians, as appropriate, were required to provide written informed consent in accordance with institutional and federal guidance.
Treatment Regimen
Pharmacokinetically Guided Topotecan Dosing A two-compartment model was fit to the topotecan lactone plasma concentration using a maximum a posteriori Bayesian algorithm as implemented in ADAPT II (available at http://bmsr.usc.edu/Software/Adapt/adptmenu.html),22 with published values (mean and variance) used as the Bayesian priors.19 Model parameters estimated for each patient included the volume of the central compartment, elimination rate constant, and the intercompartment rate constants. These parameters were used to simulate the plasma concentration-time profile for each patient, from which the AUC from time zero to infinity was calculated. As in our previous studies, we used the following equation to adjust topotecan dosage: adjusted dosage (mg/m2) = current topotecan dosage (mg/m2)/current AUC x target AUC.15,19
Evaluations During Study
Response Criteria
Statistical Considerations Survival was defined as the time interval from date of study enrollment to date of death from any cause or to the last follow-up date. Event-free survival (EFS) was defined as the time interval from date of study enrollment to date of first event (relapsed or progressive disease or death from any cause) or to the last follow-up date. Survival and EFS were estimated using the Kaplan-Meier method. Fisher's exact test, the exact Wilcoxon rank sum test, and the exact Kruskal-Wallis test were used to compare characteristics between responders and nonresponders. Responders were defined as those patients who achieved at least a PR after two cycles of topotecan; nonresponders were patients who had either SD or PD after one or two cycles of topotecan.
Patient Characteristics Between March 2003 and March 2006, 37 eligible patients were enrolled; 30 of the patients were enrolled at St Jude, and the other centers enrolled one or two patients each. Twenty-six patients (70%) had FHWT, and 11 patients (30%) had diffuse AHWT. Patient and treatment characteristics for all patients and for patients by histology are listed in Table 1. Sixty percent of patients (n = 22) were female, and most patients (n = 30; 81%) were white. The median age at diagnosis of Wilms' tumor was 4.8 years, and the median age at enrollment onto the study was 6.1 years.
Study Withdrawals, Eligibility, and Assessability Seven patients discontinued treatment before the end of the second topotecan cycle as a result of PD (three patients before completing the first cycle, three patients at the end of the first cycle, and one patient during the second cycle). One patient was removed from the study during the second cycle after suffering a stroke from a hemorrhage within a frontal lobe metastasis. This patient was not assessable for response because the CNS lesion could not be accurately measured after the hemorrhage and she did not complete two full topotecan cycles. In total, 22 patients with FHWT and seven patients with AHWT completed at least two cycles of topotecan (Table 2).
Topotecan Pharmacokinetics The inter- and intrapatient variability in topotecan lactone clearance was assessed using the mixed-effects model, which allowed us to account for possible correlations between topotecan clearance and cycle with repeated measurements within each patient. The population average topotecan lactone systemic clearance was 20.7 L/h/m2, with a range of 7.8 to 43.9 L/h/m2. The estimated interpatient and intrapatient variances were 30.3% and 15.7%, respectively. This finding was consistent with several of our other studies in which interpatient variability in topotecan clearance exceeded intrapatient variability.13,25 In the 37 children enrolled onto this study, we performed a total of 127 pharmacokinetic studies. The first pharmacokinetic study in each patient (n = 37) was performed after a fixed topotecan dosage (n = 9 at 2.4 mg/m2 or n = 28 at 1.8 mg/m2). All patients studied at the initial dosage of 2.4 mg/m2 were above the topotecan target (range, 97 to 250 ng/mL*h), whereas when the initial dosage was reduced to 1.8 mg/m2, 15 patients (54%) were within the target range on first dose. In subsequent studies using pharmacokinetically guided dosing, the overall pharmacokinetic targeting success rate was 70.2% (AUCs in 59 of 84 assessable studies were in the target range), although the target AUC was ultimately achieved in all cycles. The median topotecan dosage in the cycles in which the target AUC range was achieved was 1.8 mg/m2 (range, 0.7 to 3.2 mg/m2). Because this patient population was likely to have altered renal function and potentially decreased topotecan clearance (and elevated topotecan AUC values), one concern was that these patients would be overdosed. However, only 30 pharmacokinetic studies (24%) showed AUCs that were above the target range (ie, > 90 ng/mL*h), and only 19 (15%) showed AUCs that were more than 10% above the upper end of the target range. All of the AUCs in these patients were brought within the target with further pharmacokinetic studies. Conversely, only eight pharmacokinetic studies (6%) were more than 10% below the lower end of the target range (ie, < 60 ng/mL*h). Of these eight studies, three were with the initial fixed topotecan dosage, and the remaining five occurred after course 1, dose 2 (n = 1); course 2, dose 1 (n = 2); course 2, dose 3 (n = 1); and course 3, dose 1 (n = 1). In all eight studies, the topotecan target value was attained on subsequent pharmacokinetic studies.
Topotecan Response
Twelve (32%) of 37 patients were alive with a median follow-up time of 11.7 months (range, 1.9 to 37.7 months). Six of the survivors had no evidence of disease at last follow-up, and six were alive with disease. All survivors had been seen or contacted within 10 months of the analysis. Estimates of survival and EFS for all patients at 1 year were 29.5% ± 8.3% and 16.4% ± 6.1%, respectively. Table 4 lists patient characteristics among responders and nonresponders for the 36 assessable patients. The only significant difference between responders versus nonresponders was a longer time from initial diagnosis to topotecan study therapy (median, 30.5 v 11.9 months, respectively) and a longer time from last treatment to study therapy (median, 3.2 v 1.3 months, respectively). We were not able to detect a relationship between topotecan systemic exposure and antitumor response (data not shown), given that we maintained a narrow range of systemic exposure values (AUC).
Topotecan Toxicity Table 5 lists the most common grade 3 and 4 toxicities encountered in a total of 94 cycles of topotecan administered. The main toxicity was hematologic; all 37 patients had grade 3 or 4 toxicities. The median duration of grade 3 or 4 neutropenia was 13 days per episode (range, 2 to 31 days), and the median duration of grade 3 or 4 thrombocytopenia was 7.5 days (range, 1 to 40 days). There were 12 episodes of grade 3 bleeding/hemorrhage associated with thrombocytopenia, consisting mostly of skin bruises, nosebleeds, and mucosal bleeds. As described earlier, one patient had hemorrhage into a brain metastasis. There were 61 admissions for febrile neutropenia reported in 27 patients. Thirteen patients (35%) had a total of 18 episodes of documented infection (six catheter-related infections, two infections without neutropenia, and 10 episodes related to neutropenia). Renal toxicity consisted mainly of electrolyte imbalance partly attributable to the patients' underlying renal disease and previous therapy. One patient had a creatinine of 3.5 mg/dL at study entry and had PD that compromised the function of her sole remaining kidney, leading to grade 3 creatinine elevation. There were no toxic deaths.
This study demonstrates that topotecan has significant activity in children with FHWT when administered on a protracted schedule. The 48% response rate is especially promising given that the responses were observed in a population of heavily pretreated patients whose disease progressed after at least one salvage chemotherapy regimen. The response rate is comparable to response rates seen with other single agents that are commonly used for the treatment of Wilms' tumor including ifosfamide (20% to 50%),26-28 etoposide (42%),29 carboplatin (52%),30 and doxorubicin (54%).31 Among patients with AHWT, two responses were seen among 11 patients. Although the study was not statistically powered to assess response rate in patients with AHWT, the results suggest that topotecan has modest activity in this high-risk subgroup. The results of the present trial differ from previous topotecan trials, which showed no responses in five patients with recurrent Wilms' tumor.14,16,32 In contrast to the protracted schedule [(daily x 5) x 2] that we describe, topotecan was administered on a daily x 5 schedule (2 mg/m2/d) or as a 72-hour continuous infusion (1.3 to 1.9 mg/m2/d) in the earlier trials. It is possible that the higher cumulative topotecan dosage in the current trial improved the response rate. It is also possible that the protracted topotecan schedule was more active than the shorter schedules used in the previous studies. The selective cytotoxic action of the topoisomerase I poisons during S phase suggests that prolonged exposure to these drugs would maximize the number of cells susceptible to drug-induced death.11,33 Our study featured pharmacokinetically guided dosing of topotecan. The Wilms' tumor patient population was ideal for individualized topotecan therapy because the patients had only one kidney, and topotecan primarily undergoes renal elimination. The interpatient variance in topotecan lactone clearance was 30.2%, and a range of dosages (0.7 to 3.2 mg/m2; median, 1.8 mg/m2) was required to achieve the desired AUC. Despite this variability, only 15% of pharmacokinetic studies showed topotecan AUC values more than 10% above the upper end of the target range, and only 6% of studies showed AUC values more than 10% below the lower end of the target range. It would be helpful to have a reliable predictor of topotecan clearance (eg, serum creatinine or glomerular filtration rate), but no predictive relationship could be established (data not shown). To guide future use of topotecan in patients with recurrent Wilms' tumor, we assessed predictors of topotecan response. The only significant differences between responders and nonresponders were the time from initial diagnosis to study therapy and the time from most recent treatment to study therapy. There are several potential mechanisms of resistance to topotecan, which can be inherent to the tumor or the host. Mutations in topoisomerase I,34 decreased levels of cellular topoisomerase,35-37 and decreased cellular camptothecin accumulation38 have all been described; however, studies of in vivo mechanisms of resistance were not performed, and further investigation is warranted in prospective trials. In conclusion, topotecan is active against recurrent FHWT. Introduction of topotecan using this protracted schedule to front-line trials of high-risk recurrent Wilms' tumor should be considered.
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. Employment: N/A Leadership: N/A Consultant: Clinton F. Stewart, GlaxoSmithKline Stock: N/A Honoraria: N/A Research Funds: Clinton F. Stewart, Funds, GlaxoSmithKline; Jeffrey S. Dome, Funds, GlaxoSmithKline Testimony: N/A Other: N/A
Conception and design: Monika L. Metzger, Clinton F. Stewart, Burgess B. Freeman III, Fredric A. Hoffer, Jianrong Wu, Najat C. Daw, Jeffrey S. Dome Administrative support: Jeffrey S. Dome Provision of study materials or patients: Max J. Coppes, Ronald Grant, Murali Chintagumpala, Elizabeth A. Mullen, Carlos Alvarado, Najat C. Daw, Jeffrey S. Dome Collection and assembly of data: Monika L. Metzger, Clinton F. Stewart, Burgess B. Freeman III, Fredric A. Hoffer, Elizabeth A. Mullen, Jeffrey S. Dome Data analysis and interpretation: Monika L. Metzger, Clinton F. Stewart, Burgess B. Freeman III, Catherine A. Billups, Jianrong Wu, Jeffrey S. Dome Manuscript writing: Monika L. Metzger, Clinton F. Stewart, Najat C. Daw, Jeffrey S. Dome Final approval of manuscript: Monika L. Metzger, Clinton F. Stewart, Burgess B. Freeman III, Fredric A. Hoffer, Max J. Coppes, Carlos Alvarado, Najat C. Daw, Jeffrey S. Dome
We thank Victor M. Santana, MD, for his insightful discussions and Debbie Poe for her outstanding data management.
Supported by Grants No. CA-21765 and CA-23099 from the National Institutes of Health, grants from the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, and a research grant from GlaxoSmithKline. Presented in part at the 38th Congress of the International Society of Pediatric Oncology, September 17-21, 2006, Geneva, Switzerland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Dome JS, Liu T, Krasin M, et al: Improved survival for patients with recurrent Wilms tumor: The experience at St. Jude Children's Research Hospital. J Pediatr Hematol Oncol 24:192-198, 2002[CrossRef][Medline] 2. Dome JS, Cotton CA, Perlman EJ, et al: Treatment of anaplastic histology Wilms' tumor: Results from the Fifth National Wilms' Tumor Study. J Clin Oncol 24:2352-2358, 2006 3. Green DM, Beckwith JB, Breslow NE, et al: Treatment of children with stages II to IV anaplastic Wilms' tumor: A report from the National Wilms' Tumor Study Group. J Clin Oncol 12:2126-2131, 1994 4. Garaventa A, Hartmann O, Bernard JL, et al: Autologous bone marrow transplantation for pediatric Wilms' tumor: The experience of the European Bone Marrow Transplantation Solid Tumor Registry. Med Pediatr Oncol 22:11-14, 1994[Medline] 5. Pein F, Michon J, Valteau-Couanet D, et al: High-dose melphalan, etoposide, and carboplatin followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms' tumor: A French Society of Pediatric Oncology study. J Clin Oncol 16:3295-3301, 1998[Abstract] 6. Campbell AD, Cohn SL, Reynolds M, et al: Treatment of relapsed Wilms' tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: The experience at Children's Memorial Hospital. J Clin Oncol 22:2885-2890, 2004 7. Green DM, Cotton CA, Malogolowkin M, et al: Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group. Pediatr Blood Cancer 48:493-499, 2007[CrossRef][Medline] 8. Grundy P, Breslow N, Green DM, et al: Prognostic factors for children with recurrent Wilms' tumor: Results from the Second and Third National Wilms' Tumor Study. J Clin Oncol 7:638-647, 1989[Abstract] 9. Kremens B, Gruhn B, Klingebiel T, et al: High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma. Bone Marrow Transplant 30:893-898, 2002[CrossRef][Medline] 10. Malogolowkin MH, Green DM, Cotton C, et al: Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D and doxorubicin: A report from the National Wilms Tumor Study (NWTS) Group. J Clin Oncol 23:801s, 2005 (suppl 16s, abstr 8507) 11. Bomgaars L, Berg SL, Blaney SM: The development of camptothecin analogs in childhood cancers. Oncologist 6:506-516, 2001 12. Pappo AS, Lyden E, Breneman J, et al: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: An intergroup rhabdomyosarcoma study. J Clin Oncol 19:213-219, 2001 13. Stewart CF, Iacono LC, Chintagumpala M, et al: Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor. J Clin Oncol 22:3357-3365, 2004 14. Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998[CrossRef][Medline] 15. Santana VM, Furman WL, Billups CA, et al: Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol 23:4039-4047, 2005 16. Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 18:352-361, 1996[CrossRef][Medline] 17. Houghton PJ, Stewart CF, Zamboni WC, et al: Schedule-dependent efficacy of camptothecins in models of human cancer. Ann N Y Acad Sci 803:188-201, 1996[Medline] 18. Dome JS, Neale G, Hill DA, et al: Anti-tumor activity of topotecan against Wilms tumor: Translation of a xenograft model to a phase II study. Pediatr Blood Cancer 45:432-433, 2005 19. Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633-640, 2003 20. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline] 21. Zamboni WC, Houghton PJ, Johnson RK, et al: Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion. J Pharmacol Exp Ther 284:89-94, 1998 22. D'Argenio DZ, Schumitzky A, Wolf W: Simulation of linear compartment models with application to nuclear medicine kinetic modeling. Comput Methods Programs Biomed 27:47-54, 1988[CrossRef][Medline] 23. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 24. Tan M, Xiong X: Continuous and group sequential conditional probability ratio tests for phase II clinical trials. Stat Med 15:2037-2051, 1996[CrossRef][Medline] 25. Zamboni WC, Bowman LC, Tan M, et al: Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454-460, 1999[CrossRef][Medline] 26. Pinkerton CR, Pritchard J: A phase II study of ifosfamide in paediatric solid tumours. Cancer Chemother Pharmacol 24:S13-S15, 1989 (suppl 1)[Medline] 27. Tournade MF, Lemerle J, Brunat-Mentigny M, et al: Ifosfamide is an active drug in Wilms' tumor: A phase II study conducted by the French Society of Pediatric Oncology. J Clin Oncol 6:793-796, 1988 28. Tournade MF: A phase II study of ifosfamide in the treatment of relapses in Wilms' tumor. Cancer Chemother Pharmacol 24:S31-S33, 1989 (suppl 1)[Medline] 29. Pein F, Pinkerton R, Tournade MF, et al: Etoposide in relapsed or refractory Wilms' tumor: A phase II study by the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 11:1478-1481, 1993 30. de Camargo B, Melaragno R, Saba e Silva N, et al: Phase II study of carboplatin as a single drug for relapsed Wilms' tumor: Experience of the Brazilian Wilms' Tumor Study Group. Med Pediatr Oncol 22:258-260, 1994[Medline] 31. Ragab AH, Sutow WW, Komp DM, et al: Adriamycin in the treatment of childhood solid tumors: A Southwest Oncology Group study. Cancer 36:1567-1576, 1975[CrossRef][Medline] 32. Pratt CB, Stewart C, Santana VM, et al: Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539-543, 1994[Abstract] 33. Reid RJ, Benedetti P, Bjornsti MA: Yeast as a model organism for studying the actions of DNA topoisomerase-targeted drugs. Biochim Biophys Acta 1400:289-300, 1998[Medline] 34. Tanizawa A, Beitrand R, Kohlhagen G, et al: Cloning of Chinese hamster DNA topoisomerase I cDNA and identification of a single point mutation responsible for camptothecin resistance. J Biol Chem 268:25463-25468, 1993 35. McLeod HL, Keith WN: Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity. Br J Cancer 74:508-512, 1996[Medline] 36. Saleem A, Ibrahim N, Patel M, et al: Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning. Cancer Res 57:5100-5106, 1997 37. Woessner RD, Eng WK, Hofmann GA, et al: Camptothecin hyper-resistant P388 cells: Drug-dependent reduction in topoisomerase I content. Oncol Res 4:481-488, 1992[Medline] 38. Hendricks CB, Rowinsky EK, Grochow LB, et al: Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. Cancer Res 52:2268-2278, 1992 Submitted January 26, 2007; accepted April 16, 2007.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
