Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Google Scholar
Google Scholar
Right arrow Articles by Xiong, H. Q.
Right arrow Articles by Abbruzzese, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xiong, H. Q.
Right arrow Articles by Abbruzzese, J. L.
Clinical Cancer Research Vol. 9, 2066-2071, June 2003
© 2003 American Association for Cancer Research

Clinical Trials

Phase I and Pharmacological Study of Oral 9-Aminocamptothecin Colloidal Dispersion (NSC 603071) in Patients with Advanced Solid Tumors1

Henry Q. Xiong2, Hai T. Tran, Timothy L. Madden, Robert A. Newman and James L. Abbruzzese

Departments of Gastrointestinal Medical Oncology [H. Q. X., J. L. A.], Pharmaceutical Research [H. T. T., T. L. M.], and Experimental Therapeutics [R. A. N.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: 9-Aminocamptothecin colloidal dispersion (9-ACCD; NSC 603071) is a specific inhibitor of topoisomerase I that can be given p.o. This Phase I trial was conducted to determine the toxicity profile, maximal tolerated dose, and pharmacokinetics profile, including bioavailability, of p.o. 9-ACCD in patients with advanced solid tumors.

Experimental Design: After receiving one i.v. dose of 9-ACCD, patients were treated with 9-ACCD p.o., starting with a 2-week schedule, to establish the safety. Once safety was established, patients were treated continuously for 4 weeks followed by a rest period of 2 weeks at dosages of 0.2, 0.3, 0.45, 0.56, 0.7, and 0.63 mg/m2/day. Serial blood samples were collected for the pharmacokinetics study on day 1 after the i.v. dose and day 2 after p.o. administration. Lactone and total 9-aminocamptothecin were analyzed by high-pressure liquid chromatographic assay.

Results: Thirty-two patients were treated on the study. The dose-limiting toxicity was myelosuppression at the dosage of 0.7 mg/m2/day. Other toxic effects included nausea, vomiting, fatigue, and transient elevation of the total bilirubin level. The maximal tolerated dose was 0.63 mg/m2/day. There was no objective response. The mean terminal half-life of p.o. total 9-ACCD was 1.2 ± 1.2 h, and the volume of distribution was 17.7 ± 20.6 l/m2. The mean bioavailability of total 9-ACCD was 68.1 ± 36.4%.

Conclusions: Despite good tolerance of p.o. administration, the lack of clinical activity and variable absorption of 9-ACCD suggested that further development might not be warranted.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Camptothecin, a plant alkaloid extract from the bark of a Chinese tree, Camptotheca acuminata, has antineoplastic activities (1) . Several promising analogues of this extract, including 9-AC,3 9-nitrocamptothecin, topotecan, irinotecan, karenitecin, and DX-8951f, have been purified and tested in clinical studies. Among these, topotecan and irinotecan are the only agents currently available commercially. The principal target of the camptothecins is topoisomerase I, a nuclear enzyme implicated in the cellular processes of replication, transcription, recombination, DNA repair, and chromosome segregation (2) . Camptothecins inhibit topoisomerase I by stabilizing the complex formed by the enzyme and DNA, resulting in G2 phase cell cycle arrest and cell death (3, 4, 5) . In addition, the expression of topoisomerase I is differentially elevated in tumor tissues and human tumor xenografts growing in athymic mice, making it a preferred target for antitumor therapy (6) .

Preclinical studies demonstrated that 9-AC was slightly more potent in causing DNA strand breaks and cytotoxicity against HT-29 cell lines than CPT-11 but less potent than SN38, the active metabolite of CPT-11 or camptothecin (7) . 9-AC has activity against various human tumor xenografts, including colon, breast, prostate, lung cancers, and malignant melanoma (8, 9, 10, 11) . Additional studies have demonstrated that duration of drug exposure above a threshold concentration (10 nmol/liter or 3.6 ng/ml) and frequent administration are essential for optimal antitumor activity. These observations led to initial Phase I trials using prolonged i.v. infusion and the development of a p.o. formulation, a more convenient means of achieving prolonged drug exposure (12, 13, 14) . 9-AC is water insoluble, making it challenging to create a p.o. formulation. This difficulty was overcome by two different methods: (a) a colloidal dispersion (9-ACCD, NSC 603017) and (b) PEG 1000 (9-AC PEG 1000) formulation. Preclincial studies have demonstrated that the 9-ACCD formulation retained antitumor activity. Here, we report a Phase I clinical trial and pharmacological study of p.o. 9-ACCD in patients with advanced solid tumors.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection.
Eligibility criteria included histologically or cytologically confirmed diagnosis of a solid malignancy that was refractory to current standard therapies, age ≥16 years, ECOG performance status score ≤2, estimated life expectancy of ≥12 weeks, adequate bone marrow reserve (defined as absolute neutrophil count >1,500 cells/µl and platelet count >100,000/µl), adequate hepatic function (defined as an alanine aminotransferase level less than three times the upper limit of normal for the institution), and renal function (defined as a serum creatinine level < 1.5 mg/ml). In addition, patients could not have received any chemotherapeutic agents within 4 weeks (or within 6 weeks for mitomycin-C or nitrosoureas) or radiation within 3 weeks of therapy initiation.

Dosage and Drug Administration.
On day 1 of week 1, all patients received an i.v. dose of 9-ACCD over 15 min, and then from day 2 forward, patients received 9-ACCD p.o. The administration of 9-ACCD as an i.v. infusion allowed for the determination of the absolute bioavailability of the p.o. formulation.

The starting dosage schedule of 9-ACCD was 0.1 mg/m2/day for 5 days per week x 2 weeks. Once the safety of the 2-week schedule was determined, the schedule was increased to 3 and then 4 weeks. Patients were then treated with a dosage of 0.2 mg/m2/day, which was escalated to 0.3, 0.45, 0.56, and 0.7 mg/m2/day. Patients were then treated at 0.63 mg/m2/day after DLTs were observed at 0.7 mg/m2/day. One course of treatment consisted of p.o. administration of 9-ACCD 5 days/week for four consecutive weeks, followed by a rest period of 2 weeks. Dose escalation was guided by the toxicity profile. The dosage would be increased by 100% if there was no biological activity, 50% if there was any toxicity of less than grade II severity, and 25% if grade II toxicity (or grade I neurotoxicity) was observed.

9-ACCD was packaged in two separate vials. One vial contained 9-AC mixed with dimyristoylphosphatidylcholine, dimyristoylphosphatidyl glycerol, and mannitol, and the other vial contained a special diluent of 20% dextrose in normal saline. Immediately before administration of each p.o. dose, 9-ACCD was reconstituted with the special diluent and then further diluted in juice or a cola drink to improve palatability.

Treatment Plan.
All patients underwent complete laboratory studies and assessment of disease and performance status within 2 weeks before treatment began. During the study period, patient’s history and a physical examination was performed before beginning each course of treatment. Complete blood counts were monitored biweekly, and chemistry panel was performed before each course.

Three patients were entered at each dosage level, and 3 additional patients were added on if there was occurrence of DLT (common toxicity criterion), defined as grade 4 hematological toxicity or reversible grade 3 or 4 nonmyelosupressive toxicity occurring in 33% of patients (15) . The MTD was defined as one dosage level below the dosage that induced DLTs during course 1. Tumors were evaluated for response after every course of treatment according to the WHO criteria (16) . Patients were withdrawn from the study if their disease progressed.

Pharmacokinetics.
Blood samples were collected at cycle 1 on days 1 and 2 after i.v. and p.o. administration, respectively. Samples were collected into a heparinized Vacutainer from a peripheral venous catheter at the following times: predose, 5, 10, 15, and 30 min and 1, 1.5, 2, 3, 4, 6, 8, 10–12, and 24 h after the start of 9-ACCD administration. Samples were processed within 15 min. Lactone and total 9-ACCD (lactone plus caroxylate) were isolated by using a solid phase extraction and analyzed by high-performance liquid chromatography by using a method published previously with minor modification (17) . Briefly, the drug was extracted from plasma using solid phase extraction, then separated isocratically, and detected using fluorescence detection. A second aliquot of plasma was acidified, then analyzed using the same methods to determine total 9-AC.

PK parameters were estimated by using a two-compartment structural model with the maximum likelihood of fitting measured plasma concentration versus time data for each patient. For estimation of apparent p.o. clearance, fractional absorption was also estimated.

Model selection criteria included R2, Akaike’s information criteria, and a visual inspection of the plots for goodness of fit. All PK modeling was performed using ADAPT II version 4.0 software (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA). AUC was calculated by dividing the dosage by the systemic clearance. Estimation of p.o. bioavailability was calculated by dividing the total number 9-AC AUCs of i.v. dose by the p.o. dose.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics.
In total, 37 patients entered the trial. Among them, 2 were not eligible, 3 had inevaluable data because they were withdrawn early from the study, and 2 were withdrawn from the study early because their disease progressed before completion of the first course of treatment; data from the latter 2 patients were evaluable for toxicity only. Data from the remaining 30 patients were evaluated for both toxicity and tumor response. The characteristics of the 32 patients are listed in Table 1Citation . The median age was 52 years, and the median ECOG performance status score was 1. The majority of patients had colorectal cancer (47%) and received more than three chemotherapy regimens (44%).


View this table:
[in this window]
[in a new window]
  		Table 1 Patients characteristics (n = 32)

 
Toxicity.
Table 2Citation summarizes the hematological toxicities that occurred. No DLT was observed until a dosage of 0.2 mg/m2, at which 1 patient developed grade 3 anemia. An additional patient was enrolled, and only a grade 2 anemia was observed. Therefore, dosage escalation continued. Significant neutropenia was observed at the 0.6 mg/m2 dosage level; all of the first 3 patients enrolled at this level experienced grade 2 neutropenia, necessitating the enrollment of 3 additional patients at this dosage level. However, only 1 patient developed grade 1 neutropenia. At a dose of 0.7 mg/m2, significant hematological toxicities were observed in all 3 patients, including grade 3 anemia and grade 4 neutropenia and thrombocytopenia; thus, the DLT dose was identified. Five patients were then treated at dosage of 0.63 mg/m2, and no significant toxicities were observed. Thus, the MTD was defined as 0.63 mg/m2.


View this table:
[in this window]
[in a new window]
  		Table 2 Hematological toxicitya

 
Nonhematologic toxicities, summarized in Table 3Citation , occurred infrequently and were rarely severe. Only 1 patient developed grade 3 vomiting. Five and 7 patients experienced grade 2 vomiting and nausea, respectively, whereas 1 patient developed grade 2 diarrhea, and 6 developed grade 2 constipation. Sixteen patients experienced grade 1 or 2 fatigue. Additionally, 3 patients complained of abdominal pain.


View this table:
[in this window]
[in a new window]
  		Table 3 Nonhematologic toxicity

 
Laboratory abnormalities included transient elevation of alkaline phosphatase and bilirubin concentrations in 1 and 9 patients, respectively.

Tumor Response.
Data on tumor response were available for 30 patients. No objective responses were recorded. Fourteen patients received two courses of treatment. One patient with malignant melanoma had stable disease after two courses of treatment and received one more cycle of therapy. The rest of the patients had progressive disease after having completed one course of therapy (6 weeks).

Pharmacokinetics.
Nineteen patients consented to blood sampling for PK evaluation. All PK data were obtained from the first cycle of therapy. Tables 4Citation and 5Citation summarize the PK parameters for i.v. and p.o. formulations, respectively. For the i.v. formulation, the mean clearances for 9AC-LAC and 9-AC-TOT (±SD) were 237 ± 156 ml/min/m2 and 36.3 ± 18.2 ml/min/m2, respectively. The mean terminal half-lives of 9-AC-LAC and 9-AC-TOT were 4.8 ± 1.9 and 9.1 ± 6.8 h, respectively.


View this table:
[in this window]
[in a new window]
  		Table 4 Pharmacokinetic parameters of i.v. administered 9-ACCDa

 

View this table:
[in this window]
[in a new window]
  		Table 5 Pharmacokinetic parameters of p.o. administered 9-ACCDa

 
For the p.o. administered formulations, only 15 sample sets were evaluable for PK modeling. The remaining four sets were nonevaluable because of concentrations that were well below the limit of quantitation of high-performance liquid chromatography assay. The mean clearances for 9-AC-LAC and 9-AC-TOT clearances were 317 ± 206 and 45.8 ± 30.5 ml/min/m2, respectively. The mean terminal half-lives of 9-AC-LAC and 9-AC-TOT were 6.9 ± 3.2 and 1.2 ± 1.2 h, respectively.

The bioavailability of 9-ACCD, as calculated by the amount of 9-AC-TOT, was 68.1 ± 36.4%. A good relationship was observed between the dosage level of p.o. 9-ACCD and exposure to 9-AC-TOT (Fig. 1)Citation .



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 1. Relationship between dosage of p.o. 9-ACCD and AUC.

 
Pharmacodynamics.
The myelosuppressive effect of 9-ACCD as a function of AUC is shown in Figs. 2Citation and 3Citation . There was good correlation between 9-AC-TOT AUC and the percentage decrease in the absolute neutrophil (r2 = 0.59) and platelet (r2 = 0.47) counts.



View larger version (12K):
[in this window]
[in a new window]
  		Fig. 2. Relationship between 9-AC-total AUC and the percentage decrease in the absolute neutrophil counts (ANC) after the first cycle of therapy.

 


View larger version (13K):
[in this window]
[in a new window]
  		Fig. 3. Relationship between 9-AC-total AUC and the percentage decrease in the platelet count after the first cycle of therapy.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Early preclinical studies demonstrated that the camptothecins inhibit a wide range of experimental tumors, but their clinical development has been hampered because of their insolubility in water and unpredictable serious toxicity. Subsequent studies found that an intact lactone ring (E ring) with an "S" stereoisomeric configuration at carbon 20 is essential for antitumor activity (18, 19, 20) . Understanding this relationship between structure and antitumor activity allowed the synthesis of a series of camptothecin that was more potent and less toxic than the parental compound. 9-AC is one of the camptothecin derivatives being evaluated for clinical study. One of the important observations from preclinical studies with 9-AC was that the antitumor activity of 9-AC required prolonged drug exposure above a certain threshold. Therefore, initial clinical trials focused on prolonged i.v. infusion of 9-AC. Results of several Phase I and II trials of 9-AC infusion over 72 and 120 h have been reported (12, 13, 14 , 21 , 22) . Myelosuppression was consistently reported to be the predominant adverse effect of 9-AC. The nonhematologic adverse effects included diarrhea, nausea, and vomiting. Moreover, two Phase II trials conducted in patients with colorectal cancer found no significant antitumor activity (22 , 23) .

To improve the drug exposure time, two p.o. formulations of 9-AC were developed, 9-ACCD and 9-AC PEG 1000. Preclinical studies have demonstrated that these p.o. formulations have retained the antitumor activity of 9-AC. A Phase I trial of 9-AC PEG 1000 demonstrated that the DLTs were myelosuppression and diarrhea when p.o. 9-AC was given daily in a 14-day course repeated every 21 days. The MTD was 0.84 mg/m2/day, although there was substantial interpatient variability in the AUC and bioavailability. Our study, using the ACCD formulation, found an MTD of 0.63 mg/m2/day when given daily, 5 days/week for 4 weeks, followed by a rest period of 2 weeks. Our results confirmed the previous observation that myelosuppression was the DLT, but we encountered relatively mild nonhematologic toxicity. Our PK study also found great interpatient variation in the AUC and bioavailability. A similar trial conducted by Mani et al. (25) also concluded that poor bioavailability and highly variable absorption or drug metabolism precludes further clinical development.

Although the clinical trials of 9-AC, administered both i.v. and p.o., reported disappointing results, these findings should not be surprising. Kirstein et al. (26) studied the relationship between 9-AC systemic exposure, defined as AUC, and tumor response in human solid tumor xenografts. Both protracted i.v. infusion and p.o. administration were evaluated. Those investigators concluded that the systemic exposure required to achieve an antitumor effect was in excess of that attainable in patients. Although tumors were highly sensitive to 9-AC, a valuable lesson can be learned from this, namely that it is critical to incorporate the preclinical PK and pharmacodynamics into the development of clinical trials.


   ACKNOWLEDGMENTS
 
We thank Karen F. Philips for editorial comments, Gail Bland for preparing this manuscript, and Carol Manraj for secretarial support.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by the USPHS Grant U01 CA62461. Back

2 To whom requests for reprints should be addressed, at Department of Gastrointestinal Medical Oncology, Box 426, The University of M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-2828; Fax: (713) 745-1163; E-mail: qxiong{at}mdanderson.org Back

3 The abbreviations used are: 9-AC, 9-aminocamptothecin; DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group; PEG, polyethylene glycol; MTD, maximal tolerated dose; 9-ACCD, 9-aminocamptothecin colloidal dispersion; PK, pyruvate kinase; AUC, area under the curve. Back

Received 10/ 9/02; revised 12/17/02; accepted 12/30/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Zijlstra J. G., DeJong S., DeUries E. G. E., Mulder N. H. Topoisomerases, new targets in cancer chemotherapy. Med. Oncol. Tumor Pharmacother., 7: 11-18, 1990.[Medline]
  2. Scheider E., Hsiang Y. H., Liu L. F. DNA topoisomerase as anticancer drug targets. Adv. Pharmacol., 21: 149-183, 1990.
  3. Hsiang Y., Lihou M., Liu L. Arrest of the replication forks by the stabilized topoisomerase I-DNA cleavable complex as a mechanism of cell killing by camptothecin. Cancer Res., 49: 5077-5082, 1989.[Abstract/Free Full Text]
  4. Nitiss J., Wang J. DNA-topoisomerase targeting antitumor drugs can be studied in yeast. Proc. Natl. Acad. Sci. USA, 85: 7501-7505, 1988.[Abstract/Free Full Text]
  5. Zhang H., D’Arpa P., Liu L. A model for cell killing by topoisomerase poisons. Cancer Cell, 2: 23-27, 1990.
  6. Giovanella B. C., Stehlin J. S., Wall M. E., et al DNA topoisomerase I targeted chemotherapy of human colon cancer in xenografts. Science (Wash. DC), 246: 1046-1048, 1989.[Abstract/Free Full Text]
  7. Tanizawa A., Fujimori A., Fujimori Y., Pommier Y. Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J. Natl. Cancer Inst. (Bethesda), 86: 836-842, 1994.[Abstract/Free Full Text]
  8. Potmesil M., Giovanella B. C., Liu L. F., et al Preclinical studies of DNA topoisomerase I targeted 9-amino and 10, 11-methylenedioxycamptothecin Potmesil M. Kohn K. W. eds. . DNA Topoisomerases in Cancer, 283-298, Oxford University Press New York 1991.
  9. Potmesil M., Giovanella B. C., Wall M. E., et al Preclinical and clinical development of DNA-topoisomerase inhibitors in the United States Andoh T. eds. . The International Symposium on DNA Topoisomerases in Chemotherapy, CRC Press, Inc. New York 1992.
  10. Pantazis P., Hinz H. R., Mendoza J. T., et al Complete inhibition of growth followed by death of human malignant melanoma cells in vitro and regression of human melanoma xenografts in immunodeficient mice induced by camptothecins. Cancer Res., 52: 3980-3987, 1992.[Abstract/Free Full Text]
  11. De Souza P. L., Cooper M. R., Imondi A. R., et al 9-aminocamptothecin: a topoisomerase I inhibitor with preclinical activity in prostate cancer. Clin. Cancer Res., 3: 287-294, 1997.[Abstract]
  12. Eder J. P., Supko J. G., Lynch T., et al Phase I trial of the colloidal dispersion formulation of 9-amino-20 (S)-camptothecin administered as 72-hour continuous intravenous infusion. Clin. Cancer Res., 4: 317-324, 1998.[Abstract]
  13. Vey N., Kantarjian H., Tran H., et al Phase I and Pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia. Ann. Oncol., 10: 577-583, 1999.[Abstract/Free Full Text]
  14. De Jonge M. J. A., Punt C. J. A., Gelderblom A. H., et al Phase I and pharmacologic study of oral (PEG-1000) 9-aminocamptothecin in adult patients with solid tumors. J. Clin. Oncol., 17: 2219-2226, 1999.[Abstract/Free Full Text]
  15. Leventhal B. G. Wittes R. E. eds. . Common Toxicity Criteria in Research Methods in Clinical Oncology, Raven Press New York 1988.
  16. WHO. . WHO Handbook for Reporting Results of Cancer Treatment, WHO Offset Publications Geneva 1979.
  17. Takimoto C. H., Klecker R. W., Dahut W., et al Analysis of the active lactone from 9-AC in plasma using solid-phase extraction and high-performance liquid cromatography. J. Chromatogr., 55: 97-104, 1994.
  18. Giovanella B., Hinz H. R., Kozielsik A. J., et al Complete growth inhibition of human cancer xenografts in nude mice by treatment with 20-(S)-camptothecin. Cancer Res., 51: 3052-3055, 1991.[Abstract/Free Full Text]
  19. Hertzberg R. P., Caranfa M. J., Holden K. G., et al Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J. Med. Chem., 32: 715-720, 1989.[CrossRef][Medline]
  20. Jaxel C., Kohn K. W., Wani M. C., et al Structure-activity study of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res., 49: 1465-1469, 1989.[Abstract/Free Full Text]
  21. Minami H., Lad T. E., Nicholas M. K., et al Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused 72 hours in phase II studies. Clin. Cancer Res., 5: 1325-1330, 1999.[Abstract/Free Full Text]
  22. Thomas R. R., Dahut W., Harold N. A phase I and pharmacologic study of 9-aminocamptothecin administered as a 120-h infusion weekly to adult cancer patients. Cancer Chemother. Pharmacol., 48: 215-222, 2001.[CrossRef][Medline]
  23. Pazdur R., Medgesy D. C., Winn R. J., et al Phase II trial of 9-aminocamptothecin (NSC 603071) administered as a 120-hour continuous infusion weekly for three weeks in metastatic colorectal carcinoma. Investig. New Drugs, 16: 341-346, 1999.
  24. Pitot H. C., Knost J. A., Kugler J., et al A North Central Cancer Treatment Group phase II trial of 9-aminocamptothecin in previously untreated patients with measurable metastatic colorectal carcinoma. Cancer (Phila.), 89: 1699-1705, 2000.[CrossRef][Medline]
  25. Mani S., Iyer L., Janisch L., et al Phase I clinical and pharmacokinetic study of oral 9-aminocamptothecin (NSC-603071). Cancer Chemother. Pharmacol., 42: 84-87, 1998.[CrossRef][Medline]
  26. Kirstein M. N., Houghton P. J., Richmond L. B., et al Relation between 9-aminocamptothecin systemic exposure and tumor response in human solid tumor xenografts. Clin. Cancer Res., 7: 358-366, 2001.[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
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 Google Scholar
Google Scholar
Right arrow Articles by Xiong, H. Q.
Right arrow Articles by Abbruzzese, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Xiong, H. Q.
Right arrow Articles by Abbruzzese, J. L.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation