SEARCH

SEARCH BY CITATION

Keywords:

  • irinotecan;
  • glioma;
  • topoisomerase I;
  • Phase II trial

Abstract

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinicial trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10–15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clincial evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.Cancer 2003;97(9 Suppl):2352–8. © 2003 American Cancer Society

DOI 10.1002/cncr.11304

Patients with newly diagnosed, high-grade astrocytoma or recurrent glioma rarely are treated successfully with currently available pharmaceutical agents. For those with high-grade glioma, the median survival (approximately 10–12 months) from the time of diagnosis has not been reported to have improved since the late 1970s, when the efficacy of cranial radiation therapy and carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU]) chemotherapy was established.1–3 Multiple subsequent studies with various agents used either singly or in combination with nitrosoureas have failed to improve survival.4 For patients with recurrent glioma, the outlook is even worse. Median survival times of only 3–6 months are reported in most series.5, 6 Multiple agents have been assessed for activity in these patients, with response rates usually ranging from 0–35%.7, 8 Only the nitrosoureas and temozolomide have been found to consistently demonstrate response rates > 10–15%. To our knowledge to date, no agent or combination of agents has been found to consistently prolong the survival of patients with recurrent glioma. Clearly, new agents that improve the duration and quality of life are needed for glioma patients.

Irinotecan Metabolism

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

Irinotecan (CPT-11) is a prodrug that is converted to its active metabolite, 7-ethyl-10-hydroxy camptothecin (SN-38), by de-esterification via a carboxylesterase. CPT-11 also is converted to an inactive metabolite, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin (APC), by one of the cytochrome p450 isoforms, CYP3A4. Furthermore, SN-38 is deactivated by glucuronidation catalyzed by the uridine diphosphate glucuronyltransferase isoenzyme, UGT1A1. Each of the enzymes that activates or deactivates CPT-11 may be induced or inhibited by any number of medications administered concurrently. In particular, glioma patients often require anticonvulsants that are known to induce the hepatic enzymes that metabolize CPT-11. For example, phenytoin, phenobarbital, and carbamazepine induce CYP3A4, thereby theoretically increasing metabolism to the inactive APC metabolite. The exact nature of these interactions and their clinical significance remain under investigation.

In addition to drug-induced alterations in metabolism, inherited functional polymorphisms for some of these enzymes have been identified, and there may be other alterations that have not yet been identified. For example, a mutant allele (UGT1A1*28) of UDP-glucuronosyltransferase has reduced capacity for SN-38 glucuronidation.9, 10 Similarly, the metabolism of several enzyme-inducing anticonvulsants is catalyzed by CYP2C9, which has two alleles with lower enzymatic activity compared with the wild-type.11 Reduced enzyme-inducing anticonvulsant (EIAC) metabolism may increase CYP3A4 and UGT induction and reduce the exposure of CPT-11 or SN-38. Thus, knowledge of drug metabolism enzyme genotypes may be useful in predicting individual toxicity or response to therapy.

Preclinical Rationale

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

CPT-11, a topoisomerase-I inhibitor, has recently entered clinical trials in patients with glioma based on in vitro sensitivity against human glioma cell lines. Nakatsu et al.12 demonstrated antitumor effects of SN-38 against the glioblastoma cell lines GB-1 and U-87MG and found evidence that SN-38 induced apoptosis in the cell lines examined. In vivo models also suggested the activity of CPT-11 in gliomas. Using a nude mouse subcutaneous human glioma xenograft model, Houghton et al.13 demonstrated tumor growth inhibition in mice treated with intravenous CPT-11. The glioma xenograft was derived from a glioblastoma resistant to multiple other agents, including vincristine, melphalan, doxorubicin, and cyclophosphamide. A subsequent study demonstrated statistically significant growth inhibition in multiple subcutaneous glioma xenografts as well as significantly prolonged survival in mice bearing intracranial xenografts.14 Moreover, CPT-11 and carmustine appeared to be synergistic against central nervous system tumor cell lines (unpublished data) and in human xenografts.15, 16 Given these laboratory observations, the clinical evidence that CPT-11 is active in a variety of other solid tumors, and the demonstrated need for improved therapies in glioma patients, the North Central Cancer Treatment Group (NCCTG) has developed clinical trials to assess the efficacy of CPT-11 in patients with recurrent glioma as well as in those with newly diagnosed glioblastoma multiforme. In addition, pharmacokinetic studies to examine the interactions of CPT-11 with anticonvulsants and corticosteroids currently are in progress. Additional translational studies also are in development currently to determine 1) the associations between clinical endpoints and functional polymorphisms in enzymes known to metabolize CPT-11 and anticonvulsants and 2) potential mechanisms of drug resistance. The purpose of the current study was to provide an overview of the clinical trials and translational studies that currently are active or in development in the NCCTG.

CPT-11 in Recurrent Glioma

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

The NCCTG has completed patient enrollment into 2 sequential Phase II trials designed to 1) assess the response rate to CPT-11; 2) compare distributions of time to disease progression and overall survival with the historical database of 373 patients treated on prior NCCTG trials for recurrent glioma; 3) assess toxicities associated with the use of CPT-11; 4) describe the pharmacokinetics of CPT-11 (parent compound), SN-38 (its active metabolite), SN-38 glucuronide (an inactive metabolite), and APC (an inactive metabolite); and 4) correlate pharmacologic parameters with toxicity and response to therapy. All patients provided written informed consent prior to trial participation. Follow-up of patients and additional data collection and review for quality assurance purposes were ongoing at the time of this report; therefore these results remain preliminary. In both trials, adult patients with histologic proof of intracranial glioma who demonstrated tumor growth on a magnetic resonance imaging (MRI) scan at least 8 weeks after the completion of radiation therapy and who had been receiving a stable dose of (or no) corticosteroids for ≥ 2 weeks prior to baseline MRI scan were eligible to participate, assuming adequate bone marrow, hepatic, and renal function and an Eastern Cooperative Oncology Group performance score of ≥ 2. In the first trial (Trial A), patients received intravenous irinotecan at a dose of 125 mg/m2 (in patients with no prior nitrosourea) or 100 mg/m2 (in patients with prior nitrosourea) weekly for 4 of 6 weeks. In the second trial (Trial B), patients received intravenous irinotecan at a dose of 300 mg/m2 (in patients with prior nitrosourea) or 250 mg/m2 (in patients with no prior nitrosourea) as a single dose every 3 weeks. General and neurologic history, physical examination, complete blood count, serum chemistries, and head MRI scans were required every 6 weeks for patients in Trial A and every 3 weeks for patients in Trial B. Blood samples for pharmacokinetic studies were obtained during the first cycle of treatment. Dose modifications for subsequent treatment cycles, either increases or decreases, based on neutropenia, thrombocytopenia, diarrhea, and other nonhematologic toxicities were described prospectively in the protocol. Patients continued treatment up to 36 weeks in the absence of tumor progression, prohibitive toxicity, or other comorbid complications.

Between May 1998 and May 1999, 64 patients were enrolled in the clinical trial, including 32 who were treated using the weekly dosing schedule and 32 who were treated using the every-3-weeks schedule. The median age of the patients at the time of study entry was 55.5 years in Trial A and 53 years in Trial B. The most frequent toxicities reported to date, as expected, have been neutropenia and diarrhea. The median leukocyte nadirs in the first and second trials were 4.2 cells/μL and 4.1 cells/μL, respectively. One patient in the first trial and 2 patients in the second trial developed leukocyte nadirs of < 1.0 cells/μL. One patient in Trial B died as a consequence of neutropenia and infection. Mild, moderate, and severe diarrhea occurred in 41%, 9%, and 9% of patients, respectively, on the weekly schedule, and in 31%, 13%, and 3% of patients, respectively, on the every-3-weeks schedule. Four patients (13%) in Trial B developed Grade 4 diarrhea and 2 patients developed Grade 4 emesis. Grade 4 hepatic toxicity and Grade 4 infection each occurred in one patient in Trial A (National Cancer Institute Common Toxicity Criteria version 2.0).

Of 30 patients who were evaluable for response in Trial A, 2 (7%) experienced tumor regression. Of 32 patients who were evaluable for response in Trial B, 4 (13%) responded. Thus, 6 of 62 evaluable patients (10%) responded overall. On further quality assurance review, these response rates may change.

Based on these data17 and those of Friedman et al.,18 Medicare carriers in some states have approved payment for the off-label use of CPT-11 for patients with recurrent glioma. Response rate as an endpoint can be problematic because prior surgery and radiation therapy, changes in corticosteroid dosage, and varying neuroimaging techniques can alter scan appearance and confound interpretation. In further analyses, we plan to investigate other endpoints as well, including time to disease progression and survival. These endpoints also may be influenced by patient selection variables including patient age, performance score, initial tumor histologic type and grade, and duration of diagnosis prior to study entry.5, 6 Models accounting for these variables will be utilized to compare time to disease progression and overall survival in the CPT-11 trials with the NCCTG database containing the relevant confounding variables.

Reid et al.19, 20 have previously reported preliminary results of pharmacokinetic data from these trials. High-performance liquid chromatography was used to measure plasma levels of CPT-11, SN-38, SN-38 glucuronide, and APC immediately prior to CPT-11 infusion, immediately after the infusion, then at 1 hour, 2 hours, 4 hours, and 24 hours after completion of the infusion during Cycle 1 of treatment. Pharmacokinetic data were calculated by noncompartmental analysis, and these results were compared with those from cancer patients not receiving anticonvulsants who were treated on other clinical trials employing similar regimens and assay methodology. Twenty-three of 32 patients (72%) treated on Trial A and 21 of 32 patients treated on Trial B (66%) received EIACs. As has been noted previously, interpatient variability was substantial for CPT-11 and its metabolites, with exposure varying as much as fivefold. Glioma patients receiving anticonvulsants who received either the weekly (Trial A) or the every-3-weeks (Trial B) schedule of CPT-11 were found to have slightly lower mean CPT-11 and metabolite exposures as measured by the area under the concentration time curve (AUC) for drug concentration versus time plots. Among glioma patients, multivariate regression analysis suggested that the concurrent administration of phenytoin, phenobarbital, and carbamazepine but not gabapentin was associated with increased CPT-11 clearance. These results underscore the ongoing need to incorporate pharmacokinetic analyses into future clinical trial design, as well as appropriate dose adjustment in patients receiving EIACs.

These findings are consistent with previous reports of interactions between anticonvulsants and chemotherapeutic agents such as etoposide,21 paclitaxel,22 and 9-aminocamptothecin.23 To our knowledge to date, the clinical significance of these pharmacokinetic observations has not been completely elucidated. In the NCCTG trials, there was a trend toward increased severity of neutropenia with increased SN-38 exposure, but there was not a statistically significant association found between total SN-38 exposure and toxicity or response to therapy. Further analyses of recent data were in progress at last follow-up.

CPT-11 in Glioblastoma Multiforme

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

To assess the role of CPT-11 as both a radiation sensitizer and chemosensitizer in patients with newly diagnosed glioblastoma multiforme, the NCCTG has developed a clinical trial to determine the safety and efficacy of the combination. Micromolar concentrations of camptothecin analogues have been observed to inhibit potentially lethal damage repair24–28 or sublethal damage repair26 after ionizing radiation. More specifically, irinotecan has been demonstrated to be a radiosensitizer.29–31 At 0.5 μg/mL, SN-38 enhanced radiation-induced cytotoxicity in MS-1 (small lung carcinoma) cell lines. In small cell and nonsmall cell lung carcinoma tumor xenografts, the combination of SN-38 and radiation produced significant tumor regression compared with either modality alone.29 At 2.5 μg/mL, SN-38 was reported to enhance the lethal effect of radiation in spheroids of HT-29 human colon adenocarcinoma cells, possibly through the inhibition of potentially lethal damage repair.31 Whether similar effects will be observed at the somewhat lower clinically achievable concentrations is unclear. Because to our knowledge there are no reports available to test the concurrent administration of CPT-11 and cranial radiation therapy, we have proposed 2 identical pilot trials to assess the acute toxicity of a fixed dose of CPT-11 combined with radiation, one in patients not receiving EIACs and one in patients receiving EIACs. For patients not receiving anticonvulsants, we plan to administer CPT-11 concurrently with radiation therapy, starting at the weekly dose and schedule previously shown to be safe in the Phase II trial (i.e., 125 mg/m2/week, 2 of every 3 weeks). If this is unexpectedly associated with excess toxicity, we will reduce the dose to 100 mg/m2/week. Blood samples for pharmacokinetic studies will be obtained with the primary goal being to determine whether plasma concentrations similar to those shown to produce radiosensitization in preclinical studies can be achieved. After the completion of radiation therapy, patients will receive CPT-11 at a dose of 125 mg/m2/week for 2 of every 3 weeks, along with BCNU at a dose of 100 mg/m2 every 6 weeks, based on the results of a recent Phase I trial at Duke University.32 In patients receiving EIACs, the starting dose of CPT-11 with radiation therapy will be 400 mg/m2 for 4 of 6 weeks, based on a recently completed Phase I trial conducted by the New Approaches to Brain Tumor Treatment (NABTT) CNS Consortium (unpublished data). Subsequently, patients will receive CPT-11 at a dose of 225 mg/m2 for 4 of 6 weeks, plus BCNU at a dose of 100 mg/m2 for 4 of 6 weeks. Assuming acceptable acute toxicity during the pilot portion of this trial, we will subsequently activate a Phase II trial with the primary endpoint of survivalcompared with > 1000 patients with glioblastoma multiforme treated in previous NCCTG clinical trials.

In addition to assessments for safety, efficacy, and toxicity, the translational aims of the proposed trial include confirmation that the doses administered produce plasma concentrations of SN-38 similar to those found to effect radiosensitization in preclinical studies. Furthermore, it also will be important to assess functional polymorphisms in the enzymes that metabolize both CPT-11 and anticonvulsants. Inherited differences in these enzymes might influence SN-38 exposure, thereby affecting both efficacy and toxicity. Furthermore, these evaluations will enhance our understanding of drug interactions, which may be important for patients receiving CPT-11 for other malignancies.

Efforts to understand the basis of resistance to topoisomerase-I inhibitors, including CPT-11, in the clinical setting also are important. Potential mechanisms of drug resistance identified in preclinical models include increased efflux of SN-38 from the tumor cell;33–38 reduced levels,39–42 mutations,42, 43 or posttranslational modifications44–52 of topoisomerase-I that render its inhibitors ineffective; enhanced repair of double-stranded DNA breaks induced as a consequence of topoisomerase-I poisoning;53–56 alterations in apoptotic pathways;57, 58 and redistribution of tumor cells from the S-phase (during which they are most sensitive to topoisomerase-I poisoning) to the G1 or G2 phase of the cell cycle.59–61 For many of these potential mechanisms of resistance, antibodies to key enzymes in the relevant pathways are available. Brain tumor tissue obtained from surgical procedures will be collected to assay for the expression of various polypeptides that can affect drug resistance and sensitivity. We plan to utilize assays described previously for alterations in topoisomerase levels,40 elevations in antiapoptotic bcl-2 family members,62 elevated expression of the SN-38 transporter BCRP,63 and altered regulation of the ATR/hChk1 pathway.64 The results of these assays will be examined in association with clinical endpoints to determine which, if any, of the pathways examined are associated with toxicity and response to treatment.

Pharmacokinetic Analyses: A Collaborative Effort

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

To our knowledge, there have been two Phase I and two Phase II trials conducted in adult patients with recurrent glioma from which there are pharmacokinetic analyses. These trials were conducted by the North American Brain Tumor Consortium65 and NABTT,66 Duke University, and the NCCTG. Colleagues in pharmacology and statistics from the NCCTG and Pharmacia Corporation will collect and analyze pooled pharmacokinetic and clinical data to examine the associations between anticonvulsants and corticosteroids with plasma concentrations of CPT-11 and its metabolites. If possible, they also will examine the relation between drug exposure and clinical endpoints, including toxicity and response to treatment. We believe these efforts will further our understanding of drug-drug interactions and provide meaningful data with regard to dose recommendations for patients with glioma and other malignancies who receive CPT-11 concurrently with drugs metabolized by the same enzymatic pathways.

Conclusions

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

CPT-11 appears to have promise in the treatment of glioma patients based on in vitro and in vivo preclinical models. Subsequent clinical trials have demonstrated modest activity in patients with recurrent glioma. Both preclinical models and our understanding of the mechanism of action suggest that CPT-11 may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of anticonvulsants that induce various hepatic enzymes, such as CYP3A4 and UGT1A1, alters the metabolism of CPT-11 and produces reduced exposure to the active metabolite, SN-38. Future clinical trials will need to assess these interactions prospectively to assure that therapeutic doses have been administered. Even in the absence of exposure to concurrent medications, there is substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Studies to evaluate the impact of pharmacogenomic interactions are warranted. Finally, several mechanisms of drug resistance have been hypothesized, but to our knowledge the clinical significance of these observations has not been confirmed. Evaluation of the factors that may reasonably be expected to alter drug sensitivity and resistance should be pursued in the clinical arena.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES

Pharmacia and Upjohn provided a grant to support pharmacokinetic analysis of the plasma concentration of irinotecan and its metabolites.

REFERENCES

  1. Top of page
  2. Abstract
  3. Irinotecan Metabolism
  4. Preclinical Rationale
  5. CPT-11 in Recurrent Glioma
  6. CPT-11 in Glioblastoma Multiforme
  7. Pharmacokinetic Analyses: A Collaborative Effort
  8. Conclusions
  9. Acknowledgements
  10. REFERENCES
  • 1
    Walker MD, Alexander E Jr., Hung WE, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg. 1978; 49: 333343.
  • 2
    Fine HA, Dear KBG, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer. 1993; 71: 25852597.
  • 3
    Buckner JC, Schomberg PJ, McCinnis WL, et al. A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alpha in the treatment of patients with newly diagnosed high-grade glioma. Cancer. 2001; 92: 420433.
  • 4
    Galanis E, Buckner J. Chemotherapy for high-grade gliomas. Br J Cancer. 2000; 82: 13711380.
  • 5
    Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999; 17: 2572.
  • 6
    Buckner JC, O'Fallon JR, Novotny P, Schaefer PL, Scheithauer BW. Determinants of time to progression and overall survival of patients in clinical trials for recurrent glioma. Neurooncol. 2000; 2: 276 (A30).
  • 7
    Galanis E, Buckner J. Chemotherapy of brain tumors. Curr Opin Neurol. 2000; 13: 619625.
  • 8
    Yung WK, Prados MD, Yaya-Tur R, et al. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. J Clin Oncol. 1999; 17: 27622771.
  • 9
    Ando Y, Saka H, Asai G, Sugiura S, Shimokata K, Kamataki T. UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol. 1998; 9: 845847.
  • 10
    Iyer L, Hall D, Das S, et al. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin Pharmacol Ther. 1999; 65: 576582.
  • 11
    Odani A, Hashimoto Y, Otsuki Y, et al. Genetic polymorphism of the CYP2C subfamily and its effect on the pharmacokinetics of phenytoin in Japanese patients with epilepsy. Clin Pharmacol Ther. 1997; 62: 287292.
  • 12
    Nagatsu S, Kondo S, Kondo Y, et al. Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11. Cancer Chemother Pharmacol. 1997; 39: 417423.
  • 13
    Houghton PJ, Cheshire PJ, Hallman JD 2nd, et al. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol. 1995; 36: 393403.
  • 14
    Hare CB, Elion GB, Houghton PJ, et al. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-peperidino)-carbonyloxy-camptothecin against pediatric and adult central nervous system tumor xenografts. Cancer Chemother Pharmacol. 1997; 39: 187191.
  • 15
    Castellino RC, Elion GB, Keir ST, et al. Schedule-dependent activity of irinotecan plus BCNU against human malignant glioma xenografts. Cancer Chemother Pharmacol. 2000; 45: 345349.
  • 16
    Coggins CA, Elion GB, Houghton PJ, et al. Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. Cancer Chemother Pharmacol. 1998; 41: 485490.
  • 17
    Buckner J, Reid J, Schaaf L, et al. A phase II trial of irinotecan (CPT-11) in recurrent glioma [abstract 679A]. Proc Am Soc Clin Oncol. 2000; 19: 175a.
  • 18
    Friedman HS, Petros WP, Friedman AH, et al. Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol. 1999; 17: 15161525.
  • 19
    Reid J, Buckner J, Schaaf L, et al. Pharmacokinetics of irinotecan (CPT-11) in recurrent glioma patients: results of an NCCTG Phase II trial. Proc Am Soc Clin Oncol. 1999; 18: 141a.
  • 20
    Reid JM, Buckner JC, Schaaf LF, et al. Anticonvulsants alter the pharmacokinetics of irinotecan (CPT-11) in patients with recurrent glioma [abstract 620]. Proc Am Soc Clin Oncol. 2000; 19: 160a.
  • 21
    Bagniewski PG, Reid JM, Ames MM, Bonner JA, Buckner JC, Sloan JA. Increased etoposide clearance in patients with glioma may be associated with concurrent glucocorticoid or anticonvulsant treatment (poster presentation) [abstract 1224]. Proc Am Assoc Cancer Res. 1996; 37: 179.
  • 22
    Fetell MR, Grossman SA, Fisher JD, et al. Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New approaches to brain tumor therapy central nervous system consortium. J Clin Oncol. 1997; 15: 13211328.
  • 23
    Grossman SA, Hochberg F, Fisher J, et al. Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. Cancer Chemother Pharmacol. 1998; 42: 118126.
  • 24
    Kim JH, Kim SH, Kolozsvary BS, Khil MS. Potentiation of radiation response in human carcinoma cells in vitro and murine fibrosarcoma in vivo by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat Oncol Biol Phys. 1992; 22: 515518.
  • 25
    Boothman DA, Wang M, Schea RA, Burrows HL, Strickfaden S, Owens JK. Posttreatment exposure to camptothecin enhances the lethal effects of x-rays on radioresistant human malignant melanoma cells. Int J Radiat Oncol Biol Phys. 1992: 24: 939948.
  • 26
    Ng CE, Bussey AM, Raaphorst GP. Inhibition of potentially lethal and sublethal damage repair by camptothecin and etoposide in human melanoma and cell lines. Int J Radiat Biol Oncol Phys. 1994; 66: 4957.
  • 27
    Eder JP, Wong JS, Chan V, Teicher BA. Irinotecan and radiation in vitro and in vivo. Int J Oncol. 1997; 11: 12351240.
  • 28
    Lamond JP, Wang M, Kinsella TJ, Boothman DA. Radiation lethality enhancement with 9-aminocamptothecin: comparison to other topoisomerase I inhibitors. Int J Radiat Oncol Biol Phys. 1996; 36: 369376.
  • 29
    Tamura K, Takada M, Kawase I, et al. Enhancement of tumor radio-response by irinotecan in human lung tumor xenografts. Jpn J Cancer Res. 1997; 88: 218223.
  • 30
    Sasai K, Guo GZ, Shibuya K, et al. Effects on SN-38 (an active metabolite of CPT-11) on responses of human and rodent cells to irradiation. Int J Radiat Oncol Biol Phys. 1998; 42: 785788.
  • 31
    Omura M, Torigoe S, Kubota N. SN-38, a metabolite of the camptothecin derivative CPT-11, potentiates of cytotoxic effect of radiation in human colon adenocarcinoma cells grown as spheroids. Radiother Oncol. 1997; 43: 197201.
  • 32
    Friedman HS, Quinn JA, Tourt-Uhlog S, et al. Phase I trial of CPT-11 plus BCNU in malignant glioma [abstract 253]. Proc Am Soc Clin Oncol. 2001; 20: 64a.
  • 33
    Ross DD, Yang W, Abruzzo LV, et al. Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst. 1999; 91: 429433.
  • 34
    Yang C-HJ, Horton JK, Cowan KH, Schneider E. Cross-resistance to camptothecin analogues in a mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations. Cancer Res. 1995; 55: 40044009.
  • 35
    Kellner U, Hutchinson L, Seidel A, et al. Decreased drug accumulation in a mitoxantrone-resistant gastric carcinoma cell line in the absence of p-glycoprotein. Int J Cancer. 1997; 71: 817824.
  • 36
    Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH. The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone or doxorubicin. Cancer Res. 1999; 59: 42374241.
  • 37
    Brangi M, Litman T, Ciotti M, et al. Camptothecin resistance: role of the ATP-binding cassette (ABC), mitoxantrone-resistance half-transporter (MXR), and potential for glucuronidation in MXR-expressing cells. Cancer Res. 1999; 59: 59385946.
  • 38
    Maliepaard M, van Gastelen MA, deJong LA, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 1999; 59: 45594563.
  • 39
    Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH. The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst. 1993; 85: 271291.
  • 40
    Valkov NI, Sullivan DM. Drug resistance of DNA topoisomerase I and II inhibitors in human leukemia, lymphoma, and multiple myeloma. Semin Hematol 1997; 34 (Suppl 5): 4862.
  • 41
    Rothenberg ML. Topoisomerase I inhibitors: review and update. Ann Oncol. 1997; 8: 837855.
  • 42
    Pommier Y, Leteurtre F, Fesen MR, et al. Cellular determinants of sensitivity and resistance to DNA topoisomerase inhibitors. Cancer Invest. 1994; 12: 530542.
  • 43
    Champoux JJ. Domains of human topoisomerase I and associated functions. Prog Nucleic Acid Res Mol Biol. 1998; 60: 111132.
  • 44
    Durban E, Goodenough M, Mills J, Busch H. Topoisomerase I phosphorylation in vitro and in rapidly growing Novikoff hepatoma cells. EMBO J. 1985; 4: 29212962.
  • 45
    Kaiserman HB, Ingebritsen TS, Benbow RM. Regulation of Xenopus Laevis DNA topoisomerase I activity by phosphorylation in vitro. Biochemistry. 1988; 27: 32163222.
  • 46
    Pommier Y, Kerrigan D, Hartman KD, Glazer RL. Phosphorylation of mammalian DNA topoisomerase I and activation by protein kinase C. J Biol Chem. 1990; 265: 94189422.
  • 47
    Samuels DS, Shimizu N. DNA topoisomerase I phosphorylation in murine fibroblasts treated with 12-0-tetradecanoylphorbol-13-acetate and in vitro by protein kinase C. J Biol Chem. 1992; 267: 1115611162.
  • 48
    D'Arpa P, Liu LF. Cell cycle-specific and transcription-related phosphorylation of mammalian topoisomerase I. Exp Cell Res. 1995; 217: 125131.
  • 49
    Ferro AM, Olivera BM. (Poly-ADP-ribosylation) of DNA topoisomerase I from calf thymus. J Biol Chem. 1984; 259: 547554.
  • 50
    Kasid UN, Halligan B, Liu LF, Dritschilo A, Smulson M. (Poly)ADP-Ribose)-mediated post-translational modification of chromatin-associated human topoisomerase I. Inhibitory effects on catalytic activity. J Biol Chem. 1989; 264: 1868718692.
  • 51
    Adamietz P. Poly(ADP-ribose) synthase is the major endogenous nonhistone acceptor for Poly(ADP-ribose) in alkylated rat hepatoma cells. J Biochem. 1987; 169: 365372.
  • 52
    Boothman DA, Fukunaga N, Wang M. Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Res. 1994; 54: 46184626.
  • 53
    Pouliot JJ, Yao KC, Robertson CA, Nash HA. Yeast gene for a Tyr0DNA phosphodiesterase that repairs topoisomerase I complexes. Science. 1999; 286: 552555.
  • 54
    Desai SD, Liu LF, Vazquez-Abad D, D'Arpa P. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem. 1997: 272: 2415924164.
  • 55
    Mao Y, Sun M, Desai SD, Liu LF. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci USA. 2000; 97: 40464051.
  • 56
    Fujimori A, Gupta M, Hoki Y, Pommier Y. Acquired camptothecin resistance of human breast cancer MCF-7/C4 cells with normal topoisomerase I and elevated DNA repair. Mol Pharmacol. 1996; 50: 14721478.
  • 57
    Walton MI, Whysong D, O'Connor PM, Hockenbery D, Korsmeyer SJ, Kohn LW. Constitutive expression of human Bcl-2 modulates nitrogen mustard and camptothecin-induced apoptosis. Cancer Res. 1993; 53: 18531861.
  • 58
    Ohmori T, Podack ER, Nishio K, et al. Apoptosis of lung cancer cells caused by some anti-cancer agents (MMC, CPT-11, ADM) is inhibited by bcl-2. Biochem Biophys Res Commun. 1993; 192: 3036.
  • 59
    Horwitz SB, Horwitz MS. Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Res. 1973; 33: 28342846.
  • 60
    Li LH, Fraser TJ, Olin EJ, Bhuyan BK. Action of camptothecin on mammalian cells in culture. Cancer Res. 1972: 32: 26432650.
  • 61
    D'Arpa P, Beardmore C, Liu LF. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 1990; 50: 69196924.
  • 62
    Pizao PE, Smitskamp-Wilms E, Van Ark-Otte J, et al. Antiproliferative activity of the topoisomerase I inhibitors topotecan and camptothecin, on sub- and postconfluent tumor cell cultures. Biochem Pharmacol. 1994: 48: 11451154.
  • 63
    Erlichman C, Boerner SA, Hallgren CG, et al. The HER throsine kinase inhibitor CI1033 enhances cytotoxicity of SN-38 and topotecan by inhibiting BRCP-mediated drug efflux. Cancer Res. 2001; 61: 739748.
  • 64
    Cliby WA, Lilly KK, Lewis KA, Kaufmann SH. S and G2 arrests induced by topoisomerase I poisons are dependent on ATR kinase function. J Biol Chem. 2002; 277: 15991606.
  • 65
    Prados M, Juhn J, Yng W, et al. A phase-I study of CPT-11 given every 3 weeks to patients with recurrent malignant glioma. A North American Brain Tumor Consortium study [abstract 627]. Proc Am Soc Clin Oncol. 2000; 19: 12a.
  • 66
    Gilbert MR, Supko J, Grossman SA, et al. Dose requirements, pharmacology and activity of CPT-11 in patients with recurrent high-grade glioma. A NABTT CNS Consortium trial [abstract 622]. Proc Am Soc Clin Oncol. 2000; 19: 161a.