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Pharmacokinetics and Pharmacodynamics of the Novel Marine-derived Anticancer Agent Ecteinascidin 743 in a Phase I Dose-finding Study¹

Charlotte van Kesteren¹, Esteban Cvitkovic, Adelkrim Taamma, Luis López-Lázaro, Joe M. Jimeno, Cecilia Guzman, Ron A. A. Mathôt, Jan H. M. Schellens, Jean-Louis Misset, Etienne Brain, Michael J. X. Hillebrand, Hilde Rosing and Jos H. Beijnen

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, 1066 EC, Amsterdam, the Netherlands [C. v. K., R. A. A. M., J. H. M. S., M. J. X. H., H. R., J. H. B.]; Paul Brousse Hospital, 94804 Villejuif Cedex, France [E. C., A. T., J. L. M., E. B.]; and Pharma Mar, Clinical Research and Development, 28760 Tres Cantos (Madrid), Spain [L. L-L., J. M. J., C. G.]

	ABSTRACT

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Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET-743 against different tumor types. A Phase I clinical trial was designed with ET-743 to identify the maximum tolerated dose and dose-limiting toxicities (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships with pharmacodynamics were evaluated. Adult patients with solid, resistant tumors received ET-743 as a 24-h i.v. infusion every 21 days. Blood samples were obtained during the first treatment course and in several consecutive courses. Noncompartmental pharmacokinetic analysis was performed. Relationships between pharmacokinetics and hepatic and hematological toxicities were explored. Fifty-two patients were treated at nine dose levels (50–1800 µg/m²). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 µg/m². Twenty-five patients were treated at the recommended Phase II dose of 1500 µg/m². At this dose, the mean value ± SD for total body clearance was 59 ± 31 liters/h, and the mean t_1/2 was 89 ± 41 h. Pharmacokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses. The percentage of decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentration versus time curve (AUC). Hepatic toxicity, defined as rise in alanine aminotransferase and aspartate aminotransferase, increased with dose and AUC but was reversible and not dose limiting. In conclusion, ET-743 administered as a 24-h i.v. infusion at a dose of 1500 µg/m² is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.

	INTRODUCTION

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A large proportion of the anticancer drugs currently used are derived from natural sources. They include the Vinca alkaloids, campthotecins, anthracyclins, and taxanes. During the past decade, the importance of marine organisms as a source of new materials has emerged and increased significantly (1 , 2) . Cytarabine was the first marine-derived anticancer drug marketed and is now an essential component in the treatment of acute myeloid leukemia. Several marine-derived compounds, e.g., bryostatin 1, dolastatins, and didemnin B, are now being clinically investigated as potential anticancer drugs (3, 4, 5, 6) . Didemnin B has shown activity against non-Hodgkin’s lymphoma in Phase II clinical studies (7) .

ET-743² (Fig. 1) is a representative example of a marine-derived anticancer product and was isolated from the Caribbean tunicate Ecteinascidia turbinata. More than 10 different ETs have been isolated; ET-743 was found to be a potent compound and appeared to be the most abundant in the tunicate (1) . In vitro studies have identified activity of the drug against solid tumor cell lines including melanoma, non-small cell lung, ovarian, renal, prostate, and breast cancer (8 , 9) . Furthermore, in vivo experiments including several human xenograft models in mice demonstrated potent activity against non-small cell lung, ovarian, breast, renal, and melanoma tumors (1 , 10 , 11) . Toxicity studies in rats, mice, dogs, and monkeys have shown hematological toxicity (anemia, leukopenia). Hepatic toxicity was observed as an increase in liver enzymes as well as evidence of cholestasis (1 , 8) .

View larger version (18K): [in this window] [in a new window]   Fig. 1. The chemical structure of ET-743.

The mechanism of antitumor activity of ET-743 has not been completely elucidated yet, although it appears to be related to its ability to form covalent adducts at the N2 position of guanine in the minor groove of DNA (1 , 14 , 15) . This binding interaction has been studied in more detail with nuclear magnetic resonance techniques, and it was reported that the units A and B and the carbinolamine moiety in ET-743 are responsible for the recognition of and bonding to DNA (14) . Recently, it was described that by binding to the minor groove, ET-743 bends DNA toward the major groove (16) . DNA-bound ET-743 appeared to modify the interaction between DNA and several transcription factors in which unit C of ET-743 is probably involved (15 , 17 , 18) . Furthermore, ET-743 has been found to inhibit transcriptional activation of the MDR1 gene by multiple inducers (19) . Cytotoxic activity of ET-743 may also be caused by disorganization of the microtubule filaments in the cell (20) . In addition, ET-743 has been found to block cell cycle progression in the late S and G₂-M phases (1) . A recent study also identified topoisomerase I (but not topoisomerase II) as a possible target of ET-743 (21) .

Preclinical studies indicated an increased activity of ET-743 after long-term exposure (1 , 8 , 9) . On the basis of these findings, a Phase I clinical study was designed and conducted with ET-743 administered as a 24-h infusion repeated every 3 weeks. The starting dose was based on mouse toxicology data, with a LD₁₀ of 200 µg/kg (600 µg/m² ). The objectives of this trial were to determine the MTD and the DLTs and to propose a safe RD for additional Phase II investigation. Furthermore, the pharmacokinetics of ET-743 and relationships with the pharmacodynamics were evaluated at different dose levels.

	PATIENTS AND METHODS

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Patient Population.
Eligibility criteria included a histologically or cytologically confirmed diagnosis of a solid tumor not responding to any established form of treatment. Previous chemotherapy and/or radiotherapy was allowed provided that the last treatment was at least 4 weeks before study entry or 6 weeks in case of nitrosoureas, mitomycin C, and high-dose carboplatin. All patients had acceptable bone marrow function (ANC, 2.5 x 10⁹/liter; platelets, 100 x 10⁹/liter; hemoglobin, 10 g/100 ml); adequate hepatic function (defined as serum bilirubin, <25 µM; transaminases and alkaline phosphatase, <3 x the upper normal limit, or <5 x the upper normal limit when attributable to liver metastases); and adequate renal function (serum creatinine 120 µM). Other eligibility criteria were a performance status of 2 on the Eastern Cooperative Oncology Group scale, age between 18 and 75 years, and a life expectancy of 3 months. The patients had to have a normal electrocardiogram and had to have recovered from any prior surgery. The study protocol was approved by the Medical Ethics Committee of the study center, and all of the patients gave written informed consent.

DLTs.
All of the toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (22) . DLTs were defined as any of the following events attributable to ET-743: any grade 4 toxicity (excluding alopecia and neutropenia); grade 3 toxicity (excluding emesis); grade 3 or 4 rise in AST, ALT, bilirubin, alkaline phosphatase, bile acids 3 x the upper normal limit, which have not recovered to grade 0 by day 21 and are still present at day 28; and grade 4 neutropnia lasting longer than 5 days or febrile neutropenia.

The dose at which at least two of three or three of six patients experienced DLTs was defined as the MTD. The next lower dose level below the MTD was defined as the RD for Phase II studies.

Treatment Plan and Study Design.
ET-743 was supplied by Pharma Mar S.A. (Madrid, Spain) as a white-to-pale-yellow lyophilized powder in glass vials containing 250 µg of ET-743. The contents of a vial were reconstituted with 5 ml of water per injection, and the obtained solution was diluted in an additional 60 ml of a sterile 0.9% sodium chloride solution. ET-743 was administered i.v. via an electric syringe in 24 h through a central venous access.

The starting dose in this Phase I study was 50 µg/m² , administered as a 24-h i.v. infusion every 3 weeks. Dosage escalation in the second and subsequent dose levels was based on the safety profile observed at the previous level. Three new patients were entered at each dose level. If one patient exhibited DLTs, three additional patients had to be treated.

Pharmacokinetics.
Serial blood samples (8 ml each) were collected in heparinized tubes at 15 time points: preinfusion; at 2, 6, and 23.5 h during the infusion; and at 5, 10, and 15 min and at 0.5, 1, 2, 4, 6, 9, 12, and 24 h after the end of the infusion. Plasma was obtained by immediate centrifugation of the samples (15 min, 4000 x g). The clear supernatant was transferred into a polypropylene tube and stored at -20°. At the lower dose levels (50–900 µg/m² ), only the first courses of treatment were pharmacokinetically monitored; at higher dose levels, the second and fifth courses were also sampled in the majority of the patients. Because ET-743 displays a long terminal elimination half-life (t_1/2), the sampling schedule was extended at the 1500- and 1800-µg/m² levels to obtain the complete terminal part of the curve; blood samples were then collected up to 300 h after the end of administration.

For the bioanalysis of ET-743, a method was used that couples miniaturized LC to an electrospray sample inlet (ESI) and two quadrupole mass analyzers (LC/ESI/MS/MS; Ref. 13 ). Solid-phase extraction on cyano columns was used as a sample pretreatment procedure. Dry residues were redissolved in reconstitution solvent containing the internal standard ET-729, and an aliquot was injected into the LC system. A methanol-water (75:25, v/v) mixture containing 5 mM ammonium acetate and 4 (v/v) formic acid was pumped through a C18 column with a flow rate of 200 µl/min. The column outlet was directly connected to the sample inlet without splitting. Ions were created at atmospheric pressure and were transferred to a quadrupole mass spectrometer. The method was validated over a range of 10–2500 pg/ml using 500 µl of plasma. The assay was linear over this range and provided within-day and between-day precision of <9.3% for all of the quality control samples. The average accuracy at four different concentrations ranged from 97 to 103%.

The pharmacokinetic parameters were calculated by applying a noncompartmental analysis using the pharmacokinetic WinNonlin program (Standard Edition Version 3.0, 1999). The maximum drug concentration (C_max) was derived directly from the experimental data. The terminal rate constant (k) was estimated by log-linear regression analysis of the terminal phase of the plasma concentration versus time curve. The area under the plasma concentration-time curve (AUC_inf) was determined using the log-linear trapezoidal method with extrapolation to infinity using the terminal rate constant k (C_last/k, where C_last is the last measured analyte concentration). The t_1/2 was calculated from the equation 0.693/k; total plasma clearance (Cl_tot) was determined by dividing the total administered dose (µg) by the AUC_inf. The apparent volume of distribution at steady state (Vss) was calculated as Vss = Cl_tot x MRT_inf, where MRT_inf is the mean residence time, which is determined as MRT_inf = (AUMCinf/AUCinf) - (1/2 x duration of infusion), where AUMC_inf is the area under the first moment curve with extrapolation to infinity.

Statistical Analyses.
Pharmacokinetic linearity between dose and AUC_inf of the first course was evaluated using linear regression analysis. Differences in pharmacokinetic parameters between the first, second, and fifth treatment cycles were evaluated using the paired t test. Baseline demographic and biochemical patient characteristics were examined as possible determinants of the pharmacokinetic parameters. Relationships were investigated between pharmacokinetic parameters and age, weight, body surface area, serum creatinine, creatinine clearance, and total protein, using Pearson’s correlation coefficient and linear regression. The effect of the presence of liver metastases at the start of treatment and the effect of gender on pharmacokinetic parameters were evaluated using the independent samples t test.

Statistical analyses were performed with SPSS (Statistical Product and Service Solutions, version 6.1 for Windows, 1994). All of the tests for significance were two-tailed, and the level of significance (P) was set at 0.05.

Pharmacodynamics.
The relationships between the dose or pharmacokinetic parameter (AUC_inf or C_max) and pharmacodynamics were explored using data of the first courses at all of the dose levels. For the evaluation of hepatic toxicities, the National Cancer Institute Common Toxicity Criteria grading system for AST, ALT, and alkaline phosphatase was used. Hematological toxicities were evaluated using the percentage of decrease in WBC, ANC, platelets, and hemoglobin. The percentage of decrease was calculated using the following equation:

The relationship between hematological toxicities and pharmacokinetics were fit to a sigmoidal maximum effect model (E_max; Ref. 23 ) using SPSS. The sigmoidal E_max model is given by

In this equation, E_max denotes the maximum effect, and P is the pharmacokinetic parameter of interest, P₅₀ represents the value of P that results in 50% of the E_max, and is the Hill coefficient, which describes the sigmoidity of the curve.

	RESULTS

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Patients and Treatment.
A total of 52 patients was enrolled in this study. Patient characteristics are listed in Table 1 . The following dose levels were evaluated: 50, 100, 200, 400, 600, 900, 1200, 1500, and 1800 µg/m² , administered as a 24-h i.v. infusion every 21 days. At the doses 50 to 900 µg/m² three patients were treated at each level during multiple courses; pharmacokinetic profiles were obtained during the first course. Five patients were given 1200 µg/m² , of which nine courses were pharmacokinetically monitored (five first and four second courses). Four patients received 1500 µg/m² ; blood samples were obtained in 10 courses (four first and second courses, two fifth courses). Four patients were treated with 1800 µg/m² ; in all four patients, the first and second courses were pharmacokinetically monitored. In one patient, samples were collected during the sixth course; these data were not taken into account for additional analyses. One patient started at a dose of 1800 µg/m² , and two courses were sampled; during the fifth course, which was also monitored, the patient received 1500 µg/m² . The results of the fifth cycle were not included in additional evaluations.

Pharmacokinetics.
Pharmacokinetic parameters of ET-743 at all of the dose levels and during multiple courses were calculated; mean values (±SD) are presented in Tables 2 and 3 . Plasma concentrations of all of the patients treated at 1500 µg/m² are shown in Fig. 2 . Typical plasma concentration versus time profiles at different dose levels of ET-743 are shown in Fig. 3 .

View larger version (10K): [in this window] [in a new window]   Fig. 2. Plasma concentration versus time for all of the patients treated with 1500 µg/m2 ET-743 during the first course of treatment. Solid line, mean plasma concentrations.

View larger version (16K): [in this window] [in a new window]   Fig. 3. Typical plasma concentration versus time profiles at different dose levels of ET-743. , 50 µg/m2; , 200 µg/m2; x, 400 µg/m2; •, 900 µg/m2; +, 1200 µg/m2; *, 1800 µg/m2.

View larger version (8K): [in this window] [in a new window]   Fig. 4. AUCinf versus dose level during the first course.

At both dose levels, 1200 and 1800 µg/m² , pharmacokinetic studies were performed in four patients during the first and the second courses. No statistically significant differences in any pharmacokinetic parameter could be observed between the first and second courses at both levels, which is consistent with the results at 1500 µg/m² .

Patient characteristics were investigated as determinants of interpatient pharmacokinetic variability. No significant relations could be identified between tested pharmacokinetic parameters (AUC _inf, Cl_tot, Vss, t_1/2, C_max) and age, weight, body surface area, gender, serum creatinine, creatinine clearance, and total protein levels. The presence of liver metastases did not seem to alter total body clearance of ET-743; the data revealed no significant difference in Cl_tot between patients with (n = 20) or without liver metastases (n = 32; P = 0.657).

Pharmacokinetic-Pharmacodynamic Relationships.
Transaminase levels increased with dose, AUC_inf and C_max during the first course; although less obvious, an increase in alkaline phosphatase was also noted. Patients experiencing a grade 3 or 4 increase in AST and ALT during the first course showed significantly higher values for the AUC_inf than did patients with grade 2 or lower increase in AST and ALT (P < 0.001 for AST and P = 0.002 for ALT; Fig. 5 ). For alkaline phosphatase this relationship was not significant.

View larger version (11K): [in this window] [in a new window]   Fig. 5. Mean values for the AUCinf ± SD observed in patients experiencing grade 2 or lower ALT/AST elevation () or grade 3 or higher ALT/AST elevation (). Left, ALT; right, AST.

View larger version (9K): [in this window] [in a new window]   Fig. 6. The percentage of decrease in ANC versus AUCinf. Solid line, fit of the data to sigmoidal Emax model.

	DISCUSSION

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At the dose range tested, the pharmacokinetics of ET-743 were found to be linear. Considerable interpatient variability in the pharmacokinetics of ET-743 was observed at all of the dose levels evaluated. The possible influence of patient characteristics on this variability was explored. No obvious correlations could, however, be identified between pharmacokinetic parameters and patient demographics or renal and liver function at study entry. Of note, no relationship existed between BSA and pharmacokinetic parameters. The presence of liver metastases at study entry did not alter the Cl_tot of ET-743.

Deviating mean pharmacokinetic parameters with large interpatient variability were observed at a dose of 400 µg/m² ; the mean value for AUC_inf was 39 h·ng/ml, although the median value was 14 h·ng/ml In this treatment group, one patient displayed a long t_1/2 of the drug (t_1/2 = 203 h), resulting in an extremely high value for the AUC_inf (91.6 h·ng/ml). The reason for the high AUC_inf value is unclear. Interestingly, this did not result in severe toxicity for this patient. At a dose of 1500 µg/m² , one patient experienced grade 3 asthenia and grade 4 neutropenia and thrombocytopenia with episthaxis during the second course of treatment. This serious adverse event was most likely caused by the deviating high value for the AUC_inf (205 h·ng/ml) that the patient displayed during this course. The value for the AUC_inf during the first course (60 h·ng/ml) was within the normal range.

At the lower dose levels (50–100 µg/m² ), plasma concentrations in the terminal part of the curve were less than the limit of quantitation (10 pg/ml) and, thus, could not be quantified, although a very sensitive analytical method was developed (13) . As a result, the t_1/2 of ET-743 at these doses was underestimated and markedly shorter than in the other treatment groups.

Initially, the first course of treatment of each patient was pharmacokinetically monitored. However, as the study progressed, it appeared that the AST/ALT elevations, which were grade 3 in the majority of the patients during the first two courses of treatment, diminished in the later courses. To investigate whether this rather unexpected phenomenon could be explained by changes in the pharmacokinetics of ET-743, consecutive courses were sampled as well at the three highest dose levels (1200, 1500, and 1800 µg/m² ). At all three dose levels, pharmacokinetic parameters did not differ significantly between the first and second course, which implied that repeated administration does not markedly alter the kinetics of the drug. However, at a dose of 1500 µg/m² , a significant increase in Cl_tot was observed between the first and fifth courses and between the second and fifth courses. This is most likely caused by the fact that, during the fifth courses, fewer blood samples were taken from the terminal part of the curve than in previous courses. Consequently, by using noncompartmental pharmacokinetic analysis, values of Cl_tot are overestimated. Therefore, it cannot be concluded that the decrease in the severity of ALT/AST elevation in the later courses of treatment is related to a change in the pharmacokinetic profile of ET-743.

Hepatic toxicity of ET-743 increased with dose and AUC_inf, both in frequency and severity, although it was not dose limiting because it had recovered to grade 0 before the next dose. Patients who experienced increase in AST and ALT of grade 3 or higher showed significantly higher values for AUC_inf than those with AST and ALT elevations of grade 2 or lower. The mechanism of the reversible hepatotoxicity is under current investigation. In preclinical studies, this phenomenon was also observed (1) .

The present study revealed significant correlations between the percentage of decrease in ANC and WBC and dose and pharmacokinetic parameters AUC_inf and C_max. Furthermore, the percentage of decrease in platelets was significantly correlated to AUC_inf. In general, the highest values for correlation coefficients were seen with the percentage of decrease in ANC. The relation between the dose-limiting ANC and AUC_inf could be adequately described using a sigmoidal E_max model, although considerable variability was observed. Therefore, other models (e.g., linear or logarithmic) could have been applied as well, but the sigmoidal E_max model was most obvious on biological grounds because it may be assumed that the percentage of decrease ranges from 0 to 100%. The data in this study approximately cover this range (Fig. 6) . Three patients experienced a probably insignificant increase in ANC after administration of ET-743. All three patients had relatively low baseline levels at study entry, and they were treated at the lower dose levels (100 and 400 µg/m² ). Correlations between percentage of decrease in ANC and dose (either in µg or µg/m² ) were significant as well. However, at the RD of 1500 µg/m² , large variability (10–100%) in the percentage of decrease in ANC was observed. The range of variability in the percentage of decrease was reduced (60–80%) when it was related to the value for AUC_inf at this dose (55 h·ng/ml on average), and, therefore, AUC_inf was considered a better predictor for neutropenia than dose.

To reduce the interpatient variability in AUC_inf, a benefit may be obtained from individual adaptation of the administered dose (25) . Because no relationships were found between pharmacokinetic parameters and patient demographics, dose individualization cannot be used in the first course. For consecutive cycles, however, the dose may be adapted on the basis of the pharmacokinetics in the previous cycle, because intrapatient variability was relatively small.

Data on the metabolism of ET-743 are scarce, and, thus far, the metabolic fate has not yet been elucidated. In vitro incubation experiments with ET-743 and rat and human hepatic microsomes have shown a time-dependent decrease of the drug concentration (26) , although metabolic products could not be identified. These experiments have also generated indications that demethylation may occur, because formaldehyde is formed during the incubation experiments. However, N-desmethyl ET-743 (ET-729) could not be detected. This is supported by the finding of Rosing et al., (13) that there was no ET-729 in the plasma of treated patients, which therefore allows this compound to be used as internal standard for the assay. ET-743 metabolic clearance after incubation with male rat liver microsomes appeared to be substantially higher than with female microsomal preparations (26) , which is probably caused by the male predominance of the responsible enzyme (CYP3A2) in this species. These differences in metabolism may contribute to the higher sensitivity of female rats for ET-743, as was seen in in vivo toxicity studies. It is unlikely that this difference in rate of metabolism between male and female rats could also be observed in humans because human cytochrome P450 enzymes do not exhibit such gender differences (26) . In fact, in the present clinical study, this is confirmed because no significant difference was found for Cl_tot or t_1/2 between male and female patients (P = 0.14 and 0.23, respectively).

The starting dose in this Phase I study was 50 µg/m² , which was approximately one-tenth of the LD₁₀ (or MTD) found in mice (200 µg/kg or 600 µg/m² , respectively). Dose escalation was based on the modified Fibonacci procedure. A pharmacologically guided escalation, as proposed by Collins et al. (27) was not applicable for this study because several requirements for the safe use of an accelerated escalation were not met. The administration of the drug in patients (24-h infusion) was prolonged compared with that in the preclinical studies (bolus injection). Furthermore, the mode of action of ET-743 has not been completely elucidated, and more work is needed to clarify the metabolism.

In preclinical studies, ET-743 showed potent cytotoxic activity at nanomolar concentrations (8, 9, 10) . The plasma concentrations reached in patients at the RD were of the same order of magnitude. Although differences in the schedule of administration and the possible differences in sensitivity to the drug may hinder extrapolation to patients, these are promising results for the Phase II efficacy studies.

The presented Phase I trial indicates that ET-743 administered as a 24-h i.v. infusion every 3 weeks is well tolerated; the DLTs were neutropenia and thrombocytopenia. At the dose range tested, we observed linear pharmacokinetics and considerable interpatient variability. The RD was identified at 1500 µg/m² , and Phase II studies have already commenced at this dose and schedule in different tumor types, including advanced soft tissue sarcomas, melanoma, and breast and renal cancer.

	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 To whom requests for reprints should be addressed, at Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam. Phone: 31205124657; Fax: 31205124753; E-mail: APCKS{at}SLZ.NL

² The abbreviations used are: ET, ecteinascidin; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; RD, recommended dose; AUC, area under the plasma concentration versus time curve; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ANC, absolute neutrophil count; LC, liquid chromatography.

Received 4/11/00; revised 8/ 3/00; accepted 9/ 6/00.

	REFERENCES

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1. Jimeno J. M., Faircloth G., Cameron L., Meely K., Vega E., Gómez A. , and Fernández Sousa-Faro, J. M. Progress in the acquisition of new-marine-derived anticancer compounds: development of Ecteinascidin-743 (ET-743). Drugs Future, 21: 1155-1165, 1996.
2. D’Incalci M. Some hope from marine derived natural products. Ann. Oncol., 9: 937-938, 1998.[Free Full Text]
3. Taylor S. A., Giroux D. J., Jaeckle K. A., Panella T. J., Dakhil S. R., Schold S. C. Phase II of Didemnin B in central nervous system tumors. Investig. New Drugs, 16: 331-332, 1999.[CrossRef]
4. Propper D. J., Macaulay V., O’Byrne K. J., Braybrooke J. P., Wilner S. M., Ganesan T. S., Talbot D. C., Harris A. L. A Phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer, 78: 1337-1341, 1998.[Medline]
5. Pitot H. C., McElroy E. A., Jr., Reid J. M., Windebank A. J., Sloan J. A., Erlichman C., Bagniewski P. G., Walker D. L., Rubin J., Goldberg R. M., Adjei A. A., Ames M. M. Phase I trial of dolastatin-10 (NSC 376128) with advanced solid tumors. Clin. Cancer Res., 5: 525-531, 1999.[Abstract/Free Full Text]
6. Villalona-Calero M. A., Baker S. D., Hammond L., Ayelsworth C., Eckhardt S. G., Kraynak M., Fram R., Fischkoff S., Velagapudi R., Toppmeyer D., Razvillas B., Jakimowicz K., Von Hoff D. D., Rowinsky E. Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies. J. Clin. Oncol., 16: 2770-2779, 1998.[Abstract]
7. Kucuk O., Young M., Hochster H., Haberman T., Wolf B., Cassileth P. Phase II trial of Didemnin B (DDB) in previously treated non-Hodgkin’s lymphoma (NHL): an Eastern Cooperative Oncology Group (ECOG) study (EST 1489). Proc. Am. Soc. Clin. Oncol., 15: 414 1996.
8. Ghielmini M., Colli E., Erba E., Bergamaschi D., Pampallona S., Jimeno J., Faircloth G., Sessa C. In vitro schedule dependency of myelotoxicity and cytotoxicity of Ecteinascidin 743 (ET-743). Ann. Oncol., 9: 989-939, 1998.[Abstract/Free Full Text]
9. Izbicka E., Lawrence R., Raymond E., Eckhardt G., Faircloth G., Jimeno J., Clark G., Von Hoff D. D. In vitro antitumor activity of the novel marine agent, Ecteinascidin-743 (ET-743, NSC-648766) against human tumors explanted from patients. Ann. Oncol., 9: 981-987, 1998.[Abstract/Free Full Text]
10. Valoti G., Nicoletti M. I., Pellegrino A., Jimeno J., Hendriks H., D’Incalci M., Faircloth G., Giavazzi R. Ecteinascidin-743, a new marine natural product with potent antitumour activity on human ovarian carcinoma xenografts. Clin. Cancer Res., 4: 1977-1983, 1998.[Abstract]
11. Hendriks H. R., Fiebig H. H., Giavazzi R., Langdon S. P., Jimeno J. M., Faircloth G. T. High antitumour activity of ET743 against human tumour xenografts from melanoma, non-small-cell lung and ovarian cancer. Ann. Oncol., 10: 1233-1240, 1999.[Abstract/Free Full Text]
12. Rosing H., Hillebrand M. J. X., Jimeno J. M., Gómez A., Floriano P., Faircloth G., Cameron L., Henrar R. E. C., Vermorken J. B., Bult A., Beijnen J. H. Analysis of Ecteinascidin 743, a new potent marine derived anticancer drug, in human plasma by high-performance liquid chromatography in combination with solid-phase extraction. J. Chromatogr. B, 710: 183-189, 1998.
13. Rosing H., Hillebrand M. J. X., Jimeno J. M., Gómez A., Floriano P., Faircloth G., Henrar R. E. C., Vermorken J. B., Cvitkovic E., Bult A., Beijnen J. H. Quantitative determination of Ecteinascidin 743 in human plasma by miniaturized high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. J. Mass Spectrom., 33: 1134-1140, 1998.[CrossRef][Medline]
14. Pommier Y., Kohlhagen G., Bailly C., Waring M., Mazumder A., Kohn K. W. 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, 35: 13303-13309, 1996.[CrossRef][Medline]
15. Moore B. M., Seaman F. C., Hurley L. H. NMR-based model of an Ecteinascidin 743-DNA adduct. J. Am. Chem. Soc., 119: 5475-5476, 1997.[CrossRef]
16. Zewail-Foote M., Hurley L. H. Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J. Med. Chem., 42: 2493-2497, 1999.[CrossRef][Medline]
17. Bonfanti M., La Valle,x E., Fernández Sousa-Faro J. M., Faircloth G., Caretti G., Mantonvani R., D’Incalci M. Effect of ecteinascidin-743 on the interaction between DNA binding proteins and DNA. Anticancer Drug Des., 14: 179-186, 1999.[Medline]
18. Mantonvani, R., La Valle, E., Bonfanti, M., Fernández Sousa-Faro, J. M., Faircloth, G., and D’Incalci, M. Effect of Ecteinascidin 743 (ET-743) on the interaction between transcription factors and DNA. Ann. Oncol., (Suppl. 2)9: 139, 1998.
19. Jin S., Hu Z., Scotto K. W. The antitumor agent Ecteinascidin 743 (ET743), inhibits transcriptional activation of the MDR1 gene by multiple inducers. Clin. Cancer Res., 5(Suppl.): 3790s 1999.
20. García-Rocha M., García-Gravalos M. D., Avila J. Characterisation of antimitotic products from marine organisms that disorganise the microtubule network: ecteinascidin 743, isohomohalichondrin-B and LL-15. Br. J. Cancer, 73: 875-883, 1996.[Medline]
21. Takebayashi Y., Pourquier P., Yoshida A., Kohlhagen G., Pommier Y. , Poisoning of human DNA topoisomerase I by ecteinascidin 743, an anticancer drug that selectively alkylates DNA in the minor groove. Proc. Natl. Acad. Sci. USA, 96: 7196-7201, 1999.[Abstract/Free Full Text]
22. National Cancer Institute: Guidelines for Reporting Adverse Drug Reactions. Bethesda, MD: Division of Cancer Treatment, National Cancer Institute, 1988.
23. Holford N. H. G., Sheiner L. B. Kinetics of pharmacologic response. Pharmacol. Ther., 16: 143-166, 1982.[CrossRef][Medline]
24. Cvitkovic E., Riofrio M., Goldwasser F., Delaloge S., Taamma A., Beijnen J. H., Jimeno J. M., Mekranter B., Guzman C., Brain E., Misset J. L. Final results of a Phase I study of Ecteinascidin-743 (ET-743) 24 hour (h) continuous infusion (CI) in advanced solid tumors (AST) patients (pts. ). Proc. Am. Soc. Clin. Oncol., 18: 180 1999.
25. Kobayashi K., Jodrell D. I., Ratain M. Pharmacodynamic-pharmacokinetic relationships and therapeutic drug monitoring. Cancer Surv., 17: 51-78, 1993.[Medline]
26. Kuffel M. J., Reid J. M., Ames M. M. Cytochrome P450 catalyzed metabolism of Ecteinascidin 743 by rat and human liver microsomes. Proc. Am. Assoc. Cancer Res., 38: 596 1997.
27. Collins J. M., Grieshaber C. K., Chabner B. A. Pharmacologically guided Phase I clinical trials based upon preclinical drug development. J. Natl. Cancer Inst., 82: 1321-1326, 1992.[Abstract/Free Full Text]

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