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Clinical Trials |
1 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; 2 Pharmacia Corp., Peapack, New Jersey; and 3 Pharmacia Corp., Milan, Italy
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Using an accelerated dose escalation design, patients with advanced solid tumor malignancies were treated with brostallicin administered as a 10-min i.v. infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose of brostallicin was 0.3 mg/m2/week. To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first and last infusions during cycle 1, and in cycles 2 and 4 in a limited number of patients.
Results: Fourteen patients received 32 complete cycles of brostallicin. Dose-limiting toxicity was febrile neutropenia and was observed in 3 of 5 patients treated at 4.8 mg/m2/week. The maximum tolerated dose and recommended Phase II dose was 2.4 mg/m2/week. The mean ± SD terminal half-life at the maximum tolerated dose was 4.6 ± 4.1 h. There was moderate distribution of brostallicin into tissues, and the clearance was 
20% of the hepatic blood flow. The area under the concentration time curve0-
of brostallicin increased in a dose-linear fashion. No significant relationship was observed between any plasma pharmacokinetic parameter and clinical toxicities. There were no objective responses during the trial, but 5 patients had stable disease after two cycles of treatment.
Conclusions: The dose-limiting toxicity of weekly brostallicin was neutropenia. Systemic exposure increases linearly with dose. The recommended dose for Phase II studies is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The prototypic DNA MGB distamycin A (DST) is an antibiotic with an oligopeptidic pyrrolic frame ending with an amidino moiety (Fig. 1A)
, characterized by high selectivity for TA-rich sequences (5
, 6)
. Chemically reactive moieties tethered to a DST frame have led to the development of nitrogen mustard derivatives, such as tallimustine, with improved antitumor effects (Fig. 1B
; Refs. 6
, 7
). Unfortunately, myelotoxicity was dose limiting in Phase I studies of tallimustine, preventing dose-escalation to therapeutic ranges (8
, 9)
. The newer 
-halogenoacrylamido derivatives of DST showed a substantially improved in vitro therapeutic index in comparison with tallimustine as measured by clonogenic assays on both human bone marrow and cord blood cells (10
, 11)
. The therapeutic activity of these MGBs has been ascribed to their DNA binding activity, whereas the toxicity has been attributed to the inability for human cells to repair the alkylating damage induced by these agents (7
, 12, 13, 14)
.
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-bromoacrylic derivative of DST characterized by a four-unit pyrrolocarbamoyl frame ending with a guanidino moiety (Fig. 1C)
. Brostallicin is a DNA MGB, but unlike other MGBs it is nonalkylating when assessed by Taq stop and N3 or N7 adenine alkylation assays (15)
. Accordingly, the in vitro myelotoxicity of brostallicin was markedly reduced when compared with other MGBs, but antitumor activity was retained (15
, 16)
. In vitro evaluations of brostallicin indicate potential for efficacy in refractory tumors including tumors expressing high levels of glutathione or glutathione S-transferase (GST), which has been associated with primary or acquired resistance to a number of anticancer drugs including nitrogen mustards, platinum agents, and anthracyclines (17, 18, 19, 20, 21, 22) . Brostallicin was active in tumor cells resistant to alkylating agents and camptothecin, and was also active against DNA mismatch repair-deficient tumor cells where other MGB agents have proven ineffective (16 , 23) . In preclinical animal studies there was moderate distribution of brostallicin into tissues and the area under the concentration time curve (AUC) increased slightly more than in direct proportionality to dose. Hematopoietic and hepatic toxicity were transient and dose dependent, and myelotoxicity was the dose-limiting toxicity (DLT; data from the Investigator Brochure, Pharmacia Corporation).
Clinical investigation of brostallicin as an antitumor agent is based on its provocative mechanism of action, the improved therapeutic index in preclinical models compared with other MGBs, and the efficacy of brostallicin in a broad spectrum of preclinical tumor models. The principal objectives of this open-label, nonrandomized, dose-escalation Phase I study were to: (a) determine and characterize the frequency, severity, and reversibility of the DLTs of brostallicin when administered as an i.v. infusion on days 1, 8, and 15 every 28 days in adult patients with advanced solid tumors; (b) determine the maximum tolerated dose (MTD) of brostallicin when administered on this weekly schedule to recommend a safe starting dose for Phase II studies; (c) investigate the plasma pharmacokinetic profile of brostallicin; and (d) document any antitumor activity.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years; (b) Eastern Cooperative Oncology Group performance status 
2; (c) a life-expectancy 12 weeks; (d) no prior cancer therapy within 4 weeks (6 weeks for carboplatin) and no prior treatment with nitrosoureas or mitomycin C, pelvic radiation therapy, or radiotherapy such that total bone marrow exposure was >25%; (e) resolution of all acute toxic effects from prior therapy (excluding alopecia and grade 1 neurotoxicity); (f) adequate bone marrow function defined as absolute neutrophil count (ANC) 1,500/µl, platelet count > = 100,000/µl; (g) adequate hepatic function defined as total bilirubin level within the upper limit of normal, and aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase 2.5 times the upper limit of normal; (h) adequate renal function defined as serum creatinine 1.5 times the upper limit of normal or a calculated creatinine clearance 60 ml/min; (i) no second malignancies (excluding prior cancers in remission for 5 years, surgically resected in situ cervical cancer and surgically resected nonmelanoma skin cancer); (j) no prior history of high-dose myeloablative chemotherapy requiring hematopoietic stem-cell support; (k) no pregnant women or breast feeding mothers; (l) no clinically apparent active neoplastic involvement of the central nervous system; (m) no clinically significant uncontrolled cardiac disease (e.g., congestive heart failure, angina pectoris, or myocardial infarction) within 6 months; (n) no coexisting medical problems of sufficient severity to prevent full compliance with the study such as uncontrolled hypertension, uncontrolled diabetes mellitus, uncontrolled seizure disorder, chronic obstructive pulmonary disease with hypoxia at rest, or active autoimmune disorder; and (o) patients without the mental capacity to comprehend and sign an informed consent document in compliance with institutional and federal guidelines and comply with the study requirements were excluded.
Drug Dosage and Administration.
The starting dose of brostallicin was 0.3 mg/m2/week administered i.v. as a 10-min infusion on days 1, 8, and 15 of a 28-day cycle. The starting dose corresponded to slightly less than one third of one tenth of the LD10 in mice per weekly dose. An accelerated dose escalation schema was used. This started with an accelerated phase consisting of 100% increments over the previous dose in one patient cohorts. Intrapatient dose escalation was allowed. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria Version 2.0 (24)
. When a dose level was reached where at least one Common Toxicity Criteria grade 2 toxicity occurred in the first cycle, that cohort was expanded to 3–6 patients. If no other patient experienced a grade 2 or greater toxicity, then dose escalation proceeded in 100% increments in 3 patient cohorts. If 1 of the additional patients experienced a grade 2 or greater toxicity, however, the dose escalation shifted to a modified Fibonacci scheme in 3–6 patient cohorts without intrapatient dose escalation (25)
. The MTD was defined as the highest dose at which no more than 1 of 6 new patients developed DLT during the first course. DLT was defined as: (a) ANC <500/µl lasting at least 7 days or ANC <1000/µl associated with fever or grade 3–4 sepsis; (b) platelets 10,000–25,000/µl lasting at least 7 days or of any duration associated with grade 3–4 hemorrhage, or platelets <10,000/µl for any duration; (c) nonhematologic toxicity grade 3, except for nausea and/or vomiting in the absence of an appropriate antiemetic regimen; and (d) grade 2 treatment-emergent neurotoxicity.
Brostallicin was supplied by Pharmacia Corporation as a freeze-dried powder in glass vials containing 1 mg and 10 mg of active compound. Brostallicin was diluted with 5% dextrose solution and added to an infusion bag for a total infused volume of 50 ml. The drug was infused i.v. over 10 min and protected from light during infusion. An additional 50 ml of a 5% dextrose solution was infused after completion of therapy.
Pretreatment and Follow-Up Studies.
Histories, physical examinations including pulse, blood pressure, body surface area, Eastern Cooperative Oncology Group performance status, and routine laboratory studies were performed before each treatment cycle. Routine laboratory studies included serum electrolytes, chemistries, renal and liver function tests, complete blood cell counts with differential WBCs, and urinalysis. Laboratory evaluations and vital sign assessments were also performed 3–4 days after each treatment during cycle 1 and weekly thereafter. Baseline chest X-rays and electrocardiograms were obtained before treatment. Chest X-rays were repeated after every two cycles, and electrocardiograms were repeated at the end of treatment. Pulse and blood pressure measurements were recorded before, immediately after, and 1 h after drug infusion. Toxicity evaluations were performed weekly.
The extent of malignant disease was evaluated, and measured before and after every two courses of treatment. Patients were able to continue on treatment in the absence of progressive disease. Tumor responses were defined by the "standard WHO criteria" using bidimensional measurements.
Plasma Sampling and Assay.
To study the pharmacokinetic behavior of brostallicin, serial blood samples were obtained before and after the first (day 1) and last (day 15) infusions during cycle 1. On treatment days 1 and 15, blood samples (at least 2 ml) were collected in heparin-containing vacutainer glass tubes before treatment, at infusion completion, and at 5, 15, 30 min, and 1, 2, 4, 8, 10, and 24 h after the end of treatment. When analysis of patient samples showed detectable drug levels at twice the lower limit of quantitation (0.1 ng/ml) at 24 h in 1 patients, additional samples were collected in subsequent patient cohorts at 30, 48, 72, and 96 h. The 72- and 96-h samples were not collected after the day-15 treatment. On a limited number of patients (n = 5), the evaluation of the pharmacokinetics was extended into cycles 2 and 4 applying a limited sampling procedure for pharmacokinetic evaluation, where samples were drawn at baseline, 10 min, and 2 and 4 h. The samples were centrifuged immediately after collection at 1200 x g at 4°C. The plasma was separated and stored in 0.5-ml aliquots in polypropylene tubes at -80°C pending analysis.
Determination of brostallicin plasma concentration levels was investigated using methods based on liquid chromatography-tandem mass spectrometry. The high-performance liquid chromatography apparatus consisted of a HP1100 system and a Perkin-Elmer Series 200 LC autosampler. The analytical separation was performed on a Platinum CN column (100 x 4.6 mm, 3 µm; Alltech, Milan, Italy) with a prefilter (0.5 µm x 1.5 mm; Phenomenex, Torrance, CA). A precolumn (Hypersil ODS C18; 7.5 x 4.6 mm, 5 µm; Alltech) was placed before the column. The analytical column and precolumn were maintained at 45°C. The extracts were eluted under isocratic conditions using acetonitrile:20 mM ammonium formate adjusted to pH 3.5 with 99% formic acid (80:20) at a flow rate of 1 ml/min. The LC flow was split so that 200 µl/min was directed toward the mass spectrometer interface.
The liquid chromatography-tandem mass spectrometry analysis was performed using a Perkin-Elmer Sciex API 365 mass spectrometer with a turbo ionspray interface. Multiple reaction monitoring detection in the positive ion mode was used. Precursor-to-product ion (tandem mass spectrometry) transitions of 725/257 and 729/257 were used for brostallicin and for the internal standard, respectively. The data were processed using PE-Sciex propriety software running Sample Control, version 1.3, MacQuan, version 1.6, and MassChrom, version 1.1.
Plasma samples, frozen previously at -80°C, were quickly thawed and then centrifuged at 800–900 x g for 5 min at 2–4°C. All of the vials containing plasma samples were maintained in an ice-water bath until extraction. The compound was extracted using solid phase extraction with 96-well-SPE plates [Isolute C2 (EC), 50 mg for each well] that had been primed with 0.5 ml of methanol and 0.5 ml of water, successively under vacuum. Aliquots (400 µl) from each human plasma sample were then transferred into the SPE wells, followed by the addition of 200 µl of water containing 1 µg/ml of the internal standard. Samples were drawn through the wells using a minimum amount of vacuum. After washing with 0.5 ml of water and methanol:water (10:90), the brostallicin and internal standard were eluted into a 96-well collection plate with 250 µl of 0.1% formic acid in acetonitrile, and then with 50 µl of water. The 96-well collection plate was centrifuged for 30 min at 2150 x g, and then 30 µl of the each extract was injected from the well into the high-performance liquid chromatography system.
Calibration standards were prepared by spiking aliquots of primary stock and working solutions into blank plasma in Eppendorf polypropylene vials while being cooled in an ice-water bath. Freshly prepared (unfrozen) calibration standards were always used.
Some different sets of the QC samples with five different nominal concentration levels (including out-of-range QC samples) were prepared and kept at -80°C together with human clinical samples. Out-of-range QC samples were analyzed after a 10-fold dilution with blank human plasma.
Concentrations of brostallicin are expressed in ng/ml of free base. The calibration curves were constructed by plotting the peak area ratio of the compound:internal standard (y) against its concentration using a MacQuan, version 1.6 and MassChrom 1.1. Weighted linear regression (weighting factor 1/x2) was used to fit the calibration line and, hence, to calculate brostallicin concentrations in quality control and unknown samples.
Pharmacokinetic Analyses.
The pharmacokinetic evaluations were performed with the aid of WINNonlin package (Scientific Consultant, Apex, SC). Actual sampling times and actual doses were used in the pharmacokinetic evaluations. The brostallicin plasma concentrations were interpreted in terms of noncompartmental analysis with an infusion input (model 202 of WINNonlin package).
The half-life of the terminal decay phase, t1/2, was determined by linear regression analysis of the natural-log concentration versus time curve, where t1/2 = ln (2)
/slope of the regression line. The choice of the number of points on the terminal phase was based on visual inspection of the data. The area under the plasma concentration versus time curve, AUC0-, was determined by the linear trapezoidal rule up to the last detectable concentration Ct(last), and denoted AUC 0-t (last); beyond that time the AUC 0- was determined by extrapolation from the observed C t(last) using the formula:
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The study cohort included 10 men and 4 women with a median age of 64 years. All of the patients except 2 had a performance status of 1. Nine of the 14 patients enrolled had received previous treatment with cytotoxic chemotherapy, and 4 of these subjects had received >2 prior regimens. Dose escalation proceeded from 0.3 to 4.8 mg/m2 in 100% increments (Tables 2
and 3
). There was 1 patient enrolled at each of the 0.3, 0.6, and 1.2 mg/m2 dose levels. The 2.4 mg/m2 dose level had 6 patients in the cohort. Five patients were treated at the 4.8 mg/m2 dose level, which was the highest dose tested. At the MTD, 17 cycles of brostallicin were administered, with each patient receiving at least 2 cycles of treatment (median, 2.5 cycles; range, 2–4).
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. Platelet and neutrophil nadirs occurred around day 18–22 of each cycle with duration of 7 days. Myelosuppression was not associated with cumulative dosing. Toxicity-driven cohort expansion occurred at the 4.8 mg/m2 dose level. Two of the first 4 patients treated at the 4.8 mg/m2 dose level experienced DLT. These 2 patients were both heavily pretreated with chemotherapy, whereas the other 2 who did not experience DLT had received no prior chemotherapy. It was decided to evaluate heavily pretreated (as defined in Ref. 26 ) and minimally pretreated patients separately at the 4.8 mg/m2/week dose level. The starting dose for any subsequently enrolled heavily pretreated patients was reduced to 2.4 mg/m2/week to confirm this dose level as the MTD for heavily pretreated patients, whereas accrual of minimally pretreated patients to the 4.8 mg/m2 dose level was continued. However, the next minimally pretreated patient treated at the 4.8 mg/m2 dose level experienced DLT, so the 4.8 mg/m2 dose level was considered to be a toxic level exceeding the MTD for all of the patients regardless of prior exposure to chemotherapy. The 2.4 mg/m2 dose level was fully expanded to 6 patients, heavily pretreated and minimally pretreated. Only 1 of these 6 patients experienced DLT. The 2.4 mg/m2/week dose was declared the MTD for all of the patients, and the study was closed.
The most common nonhematological adverse events were nausea, vomiting, and fatigue (Table 3)
. Grade 2 vomiting was not observed until the 2.4 mg/m2 dose level at which time prophylactic administration of antiemetic medication was initiated. Prophylactic antiemetics were effective in preventing grade 2 vomiting at the MTD. Four of 6 patients treated at 2.4 mg/m2 dose level and 4 of 5 treated at 4.8 mg/m2 dose level experienced grade 2–3 fatigue, but in no case was this considered dose limiting. Fatigue did not appear to be related to cumulative dosing of brostallicin. No subjects experienced liver toxicity, which was observed in preclinical studies. There were no patient deaths due to study drug related toxicity.
Pharmacokinetics and Pharmacodynamics.
Mean plasma concentrations of the patients obtained after the first administration of brostallicin in the first cycle are shown in Fig. 2
. The mean ± SD pharmacokinetic parameters obtained after the first and third administrations of brostallicin are reported in Tables 4
and 5
, respectively. After the end of the first infusion, the plasma concentrations of brostallicin showed a polyexponential decline. The first phase showed a rapid decline in plasma levels, as plasma levels of the compound at 1 h were <10% of the corresponding values at the end of the infusion. The mean ± SD terminal half-life of brostallicin at the MTD was 4.6 ± 4.1 h (n = 14), and the volume of distribution was 11.2 ± 7.5 liters/m2 indicating a moderate distribution of the compound into tissues. The clearance of brostallicin was 11.6 ± 2.4 liters/h/m2 and was 20% of the hepatic blood flow. There was minimal deviation from dose-linearity, as the Cend, inf, and AUC0- of brostallicin increased with increasing doses. The repeated measurements of the concentration-time profiles and the pharmacokinetic parameters, CL, Vss, and t 1/2 at later time points during cycle 1 (day 15) were similar to those after the first administration indicating no deviation from a time-independent behavior. However, 2 patients (patients 103 and 110) treated with 1.2 and 2.4 mg/m2, respectively, showed an anomalous pharmacokinetic profile on the third administration of the first cycle, reflected in the prolonged t 1/2 (Table 5)
at the 1.2 mg/m2 dose level. In both patients, a significant concentration of compound (86 and 52 ng/ml, respectively) was present before the treatment. These levels of compound were higher than the corresponding values at 24 h after dosing (16 and 11 ng/ml, respectively). A prolonged elimination phase of plasma concentrations was also observed, with low plasma concentrations in the range 23–16 ng/ml (patient 103) and 25–11 ng/ml (patient 110) on the 4–24 h time interval. This caused an apparent increase of systemic exposure to the compound compared with the previous treatments (patient 103: 87 versus 1464 ng·h/ml; patient 110: 259 versus 791 ng·h/ml after the first and third administration of the first cycle, respectively). Patient 110 participated in the limited sampling portion of the protocol during subsequent cycles of treatment, but the plasma levels of brostallicin were similar to those obtained after the first treatment of the first cycle in other patients suggesting that the anomalous behavior of the drug during cycle 1 week 3 did not persist and did not reflect a cumulative effect of the drug on its own metabolism. The reasons for the above-mentioned results remain to be elucidated, but no severe or unexpected toxicities were observed in these 2 patients during cycle 1 week 3 treatment.
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Eight of the subjects treated at the highest dose levels had pharmacokinetic assessments performed after the third (day 15) administration of brostallicin. Platelet and ANC nadirs occurred around day 18–22 of each cycle of treatment; therefore, an association between AUC and Cmax after the day-15 dose and hematological toxicity (neutropenia and thrombocytopenia) was evaluated. A trend was observed between drug exposure and hematological toxicity where higher drug exposure was associated with hematological toxicity; however, this relationship was not statistically significant (Spearman rank-order correlation analysis).
Antitumor Activity.
No objective responses were observed during this trial. Five evaluable patients had stable disease after 2 cycles of treatment. Disease progression was the reason for treatment discontinuation in 11 of the14 patients. Median duration of treatment was 2 cycles (range, 1–4). There are no patients that are still being treated with brostallicin on this study.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this Phase I clinical study, brostallicin was administered once a week for 3 consecutive weeks as a short infusion of 10 min. Dose levels ranging from 0.3 to 4.8 mg/m2 were explored using an accelerated dose escalation schema. Using the accelerated schema in which 1 patient is treated at each dose level and the dose levels are successively doubled until grade 2 or greater toxicity is observed, patient accrual and study objectives were completed in 14 months. The MTD and recommended Phase II dose was determined to be 2.4 mg/m2/week based on the principal toxicities of neutropenia, neutropenic fever, and thrombocytopenia observed at the 4.8 mg/m2 dose level. Overall, the results of the study indicated that the pharmacokinetics of brostallicin are linear with dose and characterized by a moderate clearance, volume of distribution, and half-life within the dose-range considered (0.3–4.8 mg/m2). With the exception of 2 patients, the pharmacokinetics of brostallicin were consistent between the first and third doses of the drug. No clear etiology for the atypical pharmacokinetics in patients 103 and 110 during cycle 1 has been discovered. One potential mechanism for the altered brostallicin clearance is through interaction with glutathione and glutathione-S-transferase (GST). In preclinical models, brostallicin metabolism was higher when the drug was incubated in vitro with certain GST isoenzymes (20) . Therefore, drugs that inhibit GST or glutathione could, theoretically, reduce brostallicin clearance. On a review of the concomitant medications taken by these 2 patients, especially those that may affect GST/ glutathione, it was found that both subjects were being treated with warfarin, a drug that reduces GST activity, and at least 1 of the 2 patients was using acetaminophen, which can lead to reduced levels of glutathione and elevated levels of GST (27 , 28) . However, other patients were also taking warfarin and acetaminophen, and exhibited unaltered brostallicin pharmacokinetics. Therefore, this was not considered to likely be the cause for the slow brostallicin clearance in these 2 patients. It is worth noting that the anomalous pharmacokinetic behavior was not accompanied by any enhancement of toxicity. Overall, there was no significant pharmacodynamic relationship between exposure (Cmax, AUC) to brostallicin and the incidence of myelosuppression or the occurrence of any adverse events.
Another Phase I trial of brostallicin, in which the drug was administered once every 3 weeks, yielded similar results to those reported here. Neutropenia and thrombocytopenia were dose limiting in that study, and nausea, vomiting, and fatigue were observed but not dose limiting. Pharmacokinetic evaluation yielded a similar dose-related linear increase with AUC at the dose ranges tested, clearance of 9.33 ± 2.38 liters/h/m2, terminal half-life of 4.69 ± 1.88 h, and a volume of distribution of 7.72 ± 2.62 liters/m2. When administered every 3 weeks, the AUC and Cmax of brostallicin were significantly correlated with hematological toxicity parameters (29) .
The results of this Phase I and pharmacological study indicate that treatment with brostallicin on a weekly schedule is feasible at doses up to 2.4 mg/m2/week. The MTD appears to be a biologically relevant dose, as both the plasma drug Cmax and AUC reached levels at which in vitro (IC50 range = 14.3–371 ng/ml) and in vivo cytotoxicity was observed. Other MGBs have been limited by myelotoxicity before achieving biologically relevant doses (8 , 9) . Additional investigation of this agent is indicated based on the interesting mechanisms of action and the potential for antitumor activity in tumors resistant to a variety of therapies. The recommended dose for Phase II studies using this schedule is 2.4 mg/m2 on days 1, 8, and 15 of a 28-day cycle.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
Requests for reprints: Mace L. Rothenberg, Division of Hematology/Oncology, 777 Preston Research Building, Nashville, TN 37232-6307. Phone: (615) 936-3831; Fax: (615) 343-7602; E-mail: mace. rothenberg{at}vanderbilt.edu
Received 4/24/03; revised 9/22/03; accepted 9/23/03.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-halogenoacrylic derivatives of pyrrolecarbamoyl oligomers. Farmaco., 56: 57-65, 2001.[CrossRef][Medline]
-bromoacrylic derivatives of distamycin analogues modified at the amidino moiety. Bioorg. Med. Chem. Lett., 10: 1273-1276, 2000.[CrossRef][Medline]
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