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Phase I and Pharmacokinetic Study of Brostallicin (PNU-166196), a New DNA Minor-Groove Binder, Administered Intravenously Every 3 Weeks to Adult Patients with Metastatic Cancer¹

Department of Medical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam 3075 EA, the Netherlands [A. J. t. T., J. V., A. v. d. G., M. M., C. M. H., A. S. T., M. J. A. d. J.]; Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, Maryland 20892 [A. S.]; and Pharmacia Corporation, Milano, Italy [C. F., F. F., J. T., A. A.]

	ABSTRACT

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Purpose: Brostallicin (PNU-166196) is a cytotoxic agent that binds to the minor groove of DNA with significant antitumor activity in preclinical studies. This trial was designed to determine the maximum tolerated dose, the toxicity profile, and the pharmacokinetics of Brostallicin in cancer patients.

Experimental Design: Patients were treated with escalating doses of Brostallicin ranging from 0.85 to 15 mg/m² administered as a 10-min i.v. infusion every 3 weeks. Blood samples for pharmacokinetic analysis were collected during the first and second course, and analyzed by liquid-chromatography with tandem-mass spectrometric detection.

Results: Twenty-seven evaluable patients received a total of 73 courses. Grade 4 neutropenia was the only dose-limiting toxicity at 12.5 mg/m², whereas grade 4 thrombocytopenia (1 patient) and grade 4 neutropenia (2 patients) were the dose-limiting toxicities at 15 mg/m². Other side effects, including thrombocytopenia and nausea, were generally mild. The maximum tolerated dose was defined at 10 mg/m². The clearance and terminal half-life of Brostallicin were dose-independent, with mean (±SD) values of 9.33 ± 2.38 liters/h/m² and 4.69 ± 1.88 h, respectively. There was no significant accumulation of Brostallicin with repeated administration. Significant relationships were observed between systemic exposure to Brostallicin and neutrophil counts at nadir. One partial response was observed in a patient with a gastrointestinal stromal tumor.

Conclusion: Brostallicin was found to be well tolerated, with neutropenia being the principal toxicity. The recommended dose for additional evaluation in this schedule is 10 mg/m².

	INTRODUCTION

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Brostallicin (PNU-166196) is a new synthetic -bromoacrylic derivative of distamycin A-like structures, characterized by a four-unit pyrrolcarbamoyl frame ending with a guanidine moiety (Fig. 1) . It belongs to the class of DNA MGBs,⁴ which comprises synthetic and semisynthetic compounds of very different molecular structure, acting through different mechanisms. Although MGB alkylating compounds (e.g., tallimustine, carselezin, and adozelesin) have shown excellent antitumor activity in preclinical studies, they have failed to demonstrate relevant antitumor activity in clinical trials because of severe myelotoxicity preventing the administration of potentially therapeutic doses (1, 2, 3, 4, 5, 6, 7) .

View larger version (8K): [in this window] [in a new window]   Fig. 1. Chemical structure of Brostallicin (N-[5-[[[5-[[[2-[(aminoiminomethyl)amino]ethyl]amino] carbonyl]-1-methyl-1H-pyrrol-3-yl]amino]carbonyl]-1-methyl-1H.pyrrol-3-yl]-4-[[[4-[(2-bromo-1-oxo-2-propenyl)amino]-1-methyl-1H-pyrrol-2-yl]carbonyl]amino]-1-methyl-1H-pyrrole-2-carbo-xamide hydrochloride).

In preclinical experiments, Brostallicin exerts antitumor activity against several murine and human tumor xenografts (8) Brostallicin is also highly proapoptotic (more than camptothecin) and, unlike alkylating agents and other MGBs, is fully active against DNA mismatch repair-deficient tumor cells (9, 10, 11, 12) . Brostallicin is more effective against cell sublines selected for resistance to alkylating agents and expressing high levels of GSH. Interestingly, it was found that Brostallicin reacts in vitro with GSH, but instead of causing inactivation of the drug, as one might expect, this reaction increases its cytotoxicity and the antitumor effect. The reaction between Brostallicin and GSH is catalyzed by GST with the and µ isoenzymes being more effective than the isoenzyme. Isogenic cell systems differing only for the expression of GST- isoenzyme, allowed the verification that the greater sensitivity to Brostallicin occurs not only in in vitro cultured cells but also in tumors transplanted in nude mice (13 , 14) . This might be important clinically, as GSH and GST overexpression in comparison with normal tissues occurs de novo or as a consequence of cytotoxic treatment in a number of cancers, and GST- is the most prevalent GST isoenzyme in tumors (15 , 16) .

Preclinical toxicology studies in mice and monkeys identified the hematopoietic system as the principal target of Brostallicin toxicity, mainly affecting the white cell lineage and much less frequently PLTs. The LD₁₀ of a single administration of Brostallicin in mice were 3.54 and 2.86 mg/kg in males and females, respectively (10.6 and 8.6 mg/m²).

We performed a dose-finding and pharmacological study to evaluate the toxicity of 3-weekly i.v. administration of Brostallicin, to determine the MTD, to describe the pharmacokinetics of Brostallicin, to document any antitumor effects, and to establish a dose suitable for additional Phase II evaluation of activity of the compound.

	PATIENTS AND METHODS

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Eligibility Criteria.
Patients with a cytologically or histologically confirmed diagnosis of a solid tumor refractory to standard treatment or for whom no standard treatment was available were eligible for this study. Patients with primary central nervous system neoplasm, brain or leptomeningeal metastases, or known bone marrow involvement were excluded. Additional eligibility criteria included the following: age 18 years; Eastern Cooperative Oncology Group performance status 2; life expectancy of 12 weeks; no anticancer therapy in the previous 4 weeks; adequate bone marrow function (ANC 1.5 x 10⁹/liter and PLT 100 x 10⁹/liter); adequate liver function (total bilirubin 20 µmol/liter, AST and ALT within the normal limits or up to 2.5 upper normal limit in case of liver metastasis); adequate renal function (serum creatinine <133 µmol/liter); no more than two prior heavily myelosuppressive chemotherapeutic regimens; no prior high dose chemotherapy requiring bone marrow rescue; and no radiotherapy involving >25% of bone marrow. Concomitant use of growth factors was not allowed. The institutional medical ethics committee approved the protocol. All of the patients gave written informed consent at study entry.

Treatment Assessment.
Before therapy, a complete medical history was taken, and a physical examination was performed. A complete blood count, including WBC differential, and serum chemistry, including sodium, potassium, calcium, phosphorus, urea, creatinine, total protein, albumin, glucose, alkaline phosphatase, bilirubin, AST, ALT, and -glutamyl transferase were performed, as were urine analysis, electrocardiogram, and chest X-ray. Weekly evaluations included history, physical examination, toxicity assessment according to the National Cancer Institute Common Toxicity Criteria (version date January 1998), serum chemistries, urine analysis, and electrocardiogram. Complete blood counts and liver function tests were taken twice weekly in the first three cycles and weekly thereafter. Tumor measurements were performed before treatment, after the second course or earlier in case of early progression, and every two cycles thereafter, and were evaluated according to the WHO criteria for response (17) . In case of progressive disease patients were taken off study.

Drug and Drug Administration.
Pharmacia Corporation supplied Brostallicin in vials, as freeze-dried powder for injection containing 1 and 10 mg of active drug. The vials were stored at +5°C protected from light. The content of the vials was reconstituted with 2 ml and 10 ml of dextrose 5%, respectively, using a plastic syringe. The calculated dose to be administered was put in a Baxter infusion bag containing 100 ml of dextrose 5%. The solution was kept at 2–8°C protected from light until administration. Brostallicin was administered within 4 h from drug preparation. With the exception of the first and second course, in which patients were hospitalized for pharmacokinetic sampling, patients were treated on an outpatient basis. Prophylactic antiemetics were not allowed during the first cycle of treatment.

Dosage and Dose Escalation.
Brostallicin was administered as a 10-min i.v. infusion every 3 weeks. On the basis of animal data the starting dose was 0.85 mg/m², corresponding approximately to one-tenth of the LD₁₀ in mice. Dose escalation proceeded by an accelerated phase consisting of 100% increments over the previous dose level in cohorts of 1 patient each. The accelerated scheme was chosen because of the linear pharmacokinetic behavior of the drug in animals. During the accelerated phase intrapatient dose escalation was allowed if the patient experienced only toxicities grade 0–1, and provided that 1 patient had completed one cycle at the escalated dose level, and no side effects of grade 3 and 4 were observed at the higher dose level. This accelerated phase was terminated at the first occurrence of DLT or the second instance of grade 2 toxicity in the first course. Additional dose escalations were based on the prior dose level toxicity allowing a dose escalation of 15–50% in cohorts of at least 3 patients. DLT was defined as any more than or equal to grade 3 nonhematological toxicity attributable to Brostallicin, with the exception of nausea and vomiting responding to antiemetic treatment, and a transient grade 3 increase in transaminases lasting 7 days. Treatment-related neurotoxicity of grade 2 or more was also defined as DLT. Grade 4 neutropenia for at least 7 days or complicated with infection of grade >2, febrile neutropenia, or thrombocytopenia with PLTs 10 < 25 x 10⁹/liter for 7 days, or PLTs <10 x 10⁹/liter of any duration determined the hematological DLT. The MTD (or recommended Phase II dose) was defined as the highest dose to be administered at which 0 of 6 or 1 of 6 patients experienced DLT, with the next higher dose having at least 2 of 3 or 2 of 6 patients encountering DLT. Once the MTD was reached, additional patients were treated at the same dose level, to characterize the safety profile of Brostallicin at the expected Phase II dose. If a patient encountered DLT, the dose of Brostallicin was to be decreased to the next previous level at retreatment. The treatment was resumed when ANC had recovered to >1.5 x 10⁹/liter, and the PLT count to >100 x 10⁹/liter, and nonhematological toxicity had recovered to less than grade 2. In case the toxicity had not recovered within 2 weeks of the planned retreatment time, the patient went off study.

Pharmacokinetic Analysis.
Eleven blood samples of 6 ml were taken on the first day of cycles 1 and 2 from the arm opposite of the infusion site via an i.v. canula before administration (predose); at the end of infusion; at 5, 15, and 30 min; and 1, 2, 4, 8, 10, and 24 h after the end of infusion. The blood was collected in tubes containing sodium heparin and was immediately centrifuged at 1200 x g at 4°C for 10 min. Plasma was aliquoted and stored at -80°C in the dark until analysis. Plasma samples were assayed using a specific and sensitive method based on liquid chromatography with tandem-mass spectrometric detection using a turbo-ionspray interface. The sample pretreatment procedure involved a solid-phase extraction of 400-µl sample aliquots using 96-well-solid-phase extraction plates [Isolute C2(EC); 50 mg for each well]. The deuterated version of Brostallicin ([²H₄]PNU-166196A) was used as an internal standard. The lower limit of quantitation of the assay was 0.1 ng/ml, and the overall chromatographic run time was 5 min. The assay showed an acceptable interday and intra-assay precision and accuracy (coefficient of variation <10%).

For each patient the pharmacokinetic parameters were calculated by standard noncompartmental methods. Although limited sampling time points were available up to 24 h, pyruvate kinase parameters for all of the patients, including half-lives, were calculated. The C_max was put on par with the observed concentration directly at the end of infusion as read directly from the raw data. For each patient, the AUC was calculated up to the last detectable concentration (AUC_0-tz), with the linear trapezoidal rule and extrapolated to infinity (AUC_0-inf) using the terminal rate constant (k), estimated by linear-regression analysis of the final concentration-time data. The T_1/2 was calculated as ln2/k, the total plasma CL as dose divided by AUC_0-inf, and the V as CL divided by k. T_1/2 was evaluated using at least three concentration time points of the terminal phase. V at steady state was calculated as: mean residence time x CL.

Hematological pharmacodynamics in the first cycle were evaluated using nadir values of ANCs, PLT counts, and WBC counts, determined on a twice weekly basis in all of the patients. Relationships between various exposure measures and drug-induced myelosuppression were performed using both absolute nadir values during the first treatment course or by using the percentage decrease in blood cell count at nadir. This latter variable was calculated as: % decrease = [(pretreatment count - nadir count)/pretreatment count] x 100.

Statistical Analysis.
All of the pharmacokinetic data are presented as mean values ± SD, unless stated otherwise. The relationship between peak concentration or AUC and administered absolute dose was evaluated by a least-squares linear regression analysis. The effect of drug dose on CL, V, and T_1/2 was analyzed using a Kruskal-Wallis multiple comparison test, followed by Dunn’s test to detect significantly different groups. The effect of repeated drug administration on drug CL was tested by a paired (two-tailed) Student’s t test at a hypothesized mean difference of 0. Interindividual variability in kinetic parameters was evaluated by the coefficient of variation, expressed as a percentage of the ratio of the SD and the observed mean value. For this purpose, CL was calculated using the absolute dose in mg (CL in liters/h) or the BSA-corrected dose in mg/m² (CL in liters/h/m²). The level of significance was set at P = 0.05. Statistical correlations between exposure measures and toxic side effects or patient characteristics were evaluated using Spearman’s correlation coefficient and least-squares linear regression analysis. All of the statistical evaluations were performed on the NCSS v5.X software package (J. L. Hintze, East Kaysville, UT) except the correlation analysis performed on SAS System V6.12.

	RESULTS

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Twenty-eight patients (16 male and 12 female), with a median age of 55 years were enrolled into the study between October 1999 and June 2001. Patient characteristics are listed in Table 1 . All but 3 of the patients received prior chemotherapy. Because 1 patient did not start treatment for personal reasons, 27 patients were actually treated and evaluable for toxicity. The total and median number of courses was 73 and 3 (range, 1–12). Dose levels studied were 0.85 (n = 1), 1.7 (n = 1), 3.4 (n = 3), 5.1 (n = 3), 7.5 (n = 3), 10 (n = 6), 12.5 (n = 8), and 15 mg/m² (n = 2). In 1 patient treated at 15 mg/m² the dose was reduced in the second cycle after experiencing DLT in the first cycle.

Hematological Toxicity.
Hematological toxicities observed are listed in Table 2 . Leukopenia, more specific absolute neutropenia, was dose-dependent. The neutrophil nadir was recorded in the second week with recovery during the third week in the majority of patients (recovery: in cycle 1 median 6 days, range, 2–14; all cycles median 7 days, range, 2–18). Grade 4 neutropenia was first observed at 10 mg/m². At 12.5 mg/m², 6 of 8 patients developed grade 4 neutropenia in cycle 1, lasting 8 days in 3 of these patients. The degree of leukopenia did not correspond to the degree of neutropenia, suggesting selective neutrophil damage. Neutropenia did not seem to be cumulative. Thrombocytopenia grade 1–2 was observed in 6 of 27 patients and in 21% of cycles. Six patients in total developed grade 3 thrombocytopenia over all cycles. Thrombocytopenia grade 4 occurred in only 1 patient receiving the highest dose of 15 mg/m². Thrombocytopenia did not appear to be cumulative, because 4 of 9 patients of cohort 12.5 mg/m² developed thrombocytopenia grade 3 at their first course and not in latter courses. However, the median number of courses administered was only 3. Anemia emerging during treatment grade 1–3 was observed in 21 of 27 patients (56% of cycles). Anemia grade 4 was not noted.

View larger version (14K): [in this window] [in a new window]   Fig. 2. Relationship between Cmax and dose (top), and AUC and dose (bottom).

View larger version (16K): [in this window] [in a new window]   Fig. 3. Scatterplots depicting the relationship between ANC decrements during the first time course and AUC or Cmax of Brostallicin (A, AUC; B, Cmax).

	DISCUSSION

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The current study was performed to explore the safety, tolerability, and pharmacokinetics of Brostallicin, a novel DNA MGB. The compound shows broad antitumor activity in preclinical models and a level of in vitro myelotoxicity on human hematopoietic progenitor cells dramatically reduced in comparison with that of other MGBs. It is conceivable that Brostallicin exhibits different biological properties because it may have a different ability to alkylate DNA in the minor groove with a different sequence specificity. Characterizing the pharmacological properties of Brostallicin, mechanistic studies have suggested that its antitumor activity is increased in cells with a high GSH/GST content. This finding has potential value in cancer treatment, because GSH and GST play a role in cellular resistance to different cytotoxic drugs, and the majority of human tumors display increased levels of GSH and/or GST with respect to normal tissues.

We determined (according to the protocol definitions) the MTD of Brostallicin administered by 10-min i.v. infusion given once every 3 weeks at 10 mg/m². However, because at 12.5 mg/m² only 3 of 28 courses yielded DLT (consisting of prolonged uncomplicated neutropenia grade 4), and retreatment at the same dose did not lead to recurrence of DLT, in case of carefully controlled conditions a dose of 12.5 mg/m² once every 3 weeks could also be considered. The toxicity profile of this agent is mainly determined by reversible myelotoxicity, particularly neutropenia. At 12.5 mg/m² grade 3 and 4 neutropenia was recorded in 7 of 26 cycles (27%). At the RD (10 mg/m²) grade 3 or 4 neutropenia occurred in 4 of 8 cycles (all of them in the first cycle). The nadir value occurred approximately at day 11; the median duration of grade 3 and 4 was 6.5 days (range, 3–8 days). No double WBC nadir occurred, at variance with the MGB carzelesin (18) . Nausea and vomiting were also recorded, but were well manageable with antiemetics. Special care was taken for hepatotoxicity, because in preclinical studies the liver was identified as another target of Brostallicin. In contrast to ecteinascidin-743, a currently investigated MGB, no major transaminitis was noted (19) . In any other aspect Brostallicin was well tolerated.

After the administration of Brostallicin to various animal species, plasma CL was slow (11.7, 8.0, and 12.6 ml/min/kg in mice, dogs and monkeys, respectively), and represented <25% of the hepatic blood flow (20) . The V of the central compartment exceeded the plasma volume by 5–6-fold, and the V at steady state was 310–439 ml/kg, suggesting a moderate distribution into tissues. This is in agreement with the high hydrophilic nature of this compound. In our study the CL of Brostallicin in cancer patients was similarly slow, with a mean value of <10 liters/h/m² albeit with a relatively fast T_1/2 of 5 h. As predicted from the animal pharmacokinetic data, the V at steady state was small, 10 liters/m². Thus, the pharmacokinetic results in our study in humans are in line with the results of studies in different animal species, which had clear predictive value for pharmacokinetic studies of Brostallicin and are very similar to those of tallimustine (4 , 21 , 22) .

In the present study, Brostallicin demonstrated linear and dose-independent pharmacokinetics over the total dose range studied, without any major time dependency. Repeated administrations of Brostallicin to the same cancer patient had no measurable effect on either C_max and AUC or CL, which indicates a lack of accumulation and/or autoinduction.

A moderate degree of interpatient variability in kinetic parameters was apparent, with 2-fold variation in AUC values. To explain the observed interpatient variability in Brostallicin pharmacokinetics, relationships were evaluated between individual kinetic parameters and several other patient characteristics. No clinically significant correlation was observed between C_max or AUC and BSA, serum albumin, creatinine, or age, suggesting that reduced starting doses are not required in elderly patients. Although significant Ps were obtained with the baseline and peak transaminase evaluations when correlated to pyruvate kinase parameters of C_max and AUC, low Spearman coefficients less than the absolute value of 0.7 indicate there is a minimal association between these parameters, and as such it can be concluded that these relationships are not of clinical significance. Additional analysis is clearly required, e.g., using a multiple regression approach to construct a clinically relevant model that will include patients with altered liver and/or renal function.

Relative to the absolute CL of Brostallicin (expressed in liters/h), the interpatient variability in CL remained in a similar order of magnitude after correction for the BSA of individual patients (expressed in liters/h/m²), with coefficients of variation of 30.8% and 28.5%, respectively, indicating that BSA contributes to only 7.5% of the total kinetic variability between patients. In addition, a linear-regression analysis of absolute CL of Brostallicin versus BSA did not result in a significant relationship (r = 0.23; P = 0.30). This suggests that BSA is not a significant predictor of Brostallicin CL and that flat-fixed dosing regimens might be applied in future studies without compromising overall safety profiles.

The pharmacodynamic analysis was focused on hematological toxicity, particularly the dose-limiting neutropenia. The modeling of the pharmacokinetic and pharmacodynamic data in the present study revealed a significant relation between the hematological toxicity, and both AUC and C_max of Brostallicin.

One patient with extensive liver metastases of a gastrointestinal stromal tumor, a known chemotherapy-resistant tumor type, clearly responded to the treatment with an objective partial response lasting 16 months. Two patients, 1 with synovial sarcoma and 1 with cervix cancer/non-small-cell lung cancer demonstrated disease stabilization for, respectively, 16 and 13 weeks. Phase 2 studies on Brostallicin are currently ongoing using the 3-weekly schedule.

In conclusion, the RD for Brostallicin is 10 mg/m² given once every 3 weeks. At this dose the plasma systemic exposure (AUC) is twice as high as the exposure needed in mice models to achieve antitumor effects. Alternatively, a flat/fixed dosing can be considered. The current clinical findings and the novel mechanism of action of Brostallicin suggest that additional clinical research on this agent is clearly warranted.

	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 Presented previously in part at the 20th meeting of the American Society Clinical Oncology 2001 (abstract 379).

² To whom requests for reprints should be addressed, at Department of Medical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands. Phone: 31-10-4391505; Fax: 31-10-4391003; E-mail: a.tentije{at}erasmusmc.nl

³ Present address: National Cancer Institute, Bethesda, MD 20892.

⁴ The abbreviations used are: MGB, minor groove binder; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; GSH, glutathione; GST, glutathione-S-transferase; RD, recommended dose; ANC, absolute neutrophil count; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine-aminotransferase; C_max, peak concentration; CTC, common toxicity criteria; CL, clearance; AUC, area under the plasma concentration versus time curve; T_1/2, terminal disposition half-life; V, volume of distribution; BSA, body surface area.

Received 11/13/02; revised 3/ 9/03; accepted 3/23/03.

	REFERENCES

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. D’Incalci M., Sessa C. DNA minor groove binding ligands: A new class of anticancer agents. Expert Opin. Investig. Drugs, 6: 875-884, 1997.
2. Cozzi P. Distamycin derivatives as potential anticancer agents. Drugs, 4: 573-581, 2001.[CrossRef]
3. Marchini S., Broggini S., Sessa C., D’Incalci M. Development of distamycin-related DNA binding anticancer drugs. Expert Opin. Investig. Drugs, 10: 1703-1714, 2001.[CrossRef][Medline]
4. Sessa C., Pagani O., Zurlo M. G., de Jong J., Hofmann C., Lassus M., Marrari P., Strolin Benedetti M., Cavalli F. Phase I study of the novel distamycin derivative tallimustine (FCE 24517). Ann. Oncol., 5: 901-907, 1994.[Abstract/Free Full Text]
5. Wolff I., Bench K., Beijnen J. H., Bruntsch U., Cavalli F., de Jong J., Groot Y., van Tellingen O., Wanders J., Sessa C. Phase I clinical and pharmacokinetic study of carzelesin (U-80244) given daily for five consecutive days. Clin. Cancer Res., 2: 1717-1723, 1996.[Abstract]
6. Fleming G. F., Ratain M. J., O’Brien S. M., Schilsky R. L., Hoffman P. C., Richards J. M., Vogelzang N. J., Kasunic D. A., Earhart R. H. Phase I study of adozelesin administered by 24-hour continuous intravenous infusion. J. Natl. Cancer Inst., 86: 368-372, 1994.[Abstract/Free Full Text]
7. Schwartz G. H., Aylesworth C., Stephenson J., Johnson T., Cambell E., Hammond L., Von Hoff D. D., Rowinsky E. K. Phase I trial of bizelesin using a single bolus infusion given every 28 days in patients with advanced cancer. Proc. Am. Soc. Clin. Oncol., 19: 235a 2000.
8. Geroni C., Pennella G., Capolongo L., Moneta D., Rossi R., Farao M., Marchini S., Cozzi P. Antitumor activity of PNU-166196, a novel DNA minor groove binder selected for clinical development. Proc. Am. Assoc. Cancer. Res., 41: 265 2000.
9. Ciomei M., Pastori W., Cozzi P., Geroni M. C. Induction of apoptosis with a new distamycin derivative. Proc. Am. Assoc. Cancer Res., 40: 1490 1999.
10. Giusti A. M., Moneta D., Geroni C., Farao M. In vivo induction of apotosis with PNU-166196 in human ovarian carcinoma xenografts. Proc. Am. Assoc. Cancer Res., 41: 2706 2000.
11. Geroni C., Marchini S., Galliera E., Broggini M. Efficacy of the novel DNA minor groove binding agent, Brostallicin, against drug-resistant tumor cells. Proc. Am. Assoc. Cancer Res., 720: 146 2001.
12. Colella G., Marchini S., d’Íncalci M., Brown R., Broggini M. Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents. Br. J. Cancer, 80: 338-343, 1999.[CrossRef][Medline]
13. Geroni C., Marchini S., Cozzi P., Galliera E., Ragg E., Colombo T., Battaglia R., Howard M., D’Incalci M., Broggini M. Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione. Cancer Res., 62: 2332-2336, 2002.[Abstract/Free Full Text]
14. Cozzi P., Beria I., Caldarelli M., Capolongo L., Geroni C., Mazzini S., Ragg E. Cytotoxic halogenoacrylic derivatives of distamycin A. Bioorg. Med. Chem. Lett., 10: 1269-1272, 2000.[CrossRef][Medline]
15. Shen H., Kauvar L., Tew K. D. Importance of glutathione and associated enzymes in drug response. Oncol. Res., 9: 295-302, 1997.[Medline]
16. Tsuchida S., Sato K. Glutathione transferases and cancer. Crit. Rev. Biochem. Mol. Biol., 27: 337-384, 1992.[Medline]
17. . World Health Organization: WHO Handbook for Reporting Results of Cancer Teatment. (Offset Publication No. 40), WHO Geneva, Switzerland 1979.
18. Awada A., Punt C. J., Piccart M. J., Van Tellingen O., Van Manen L., Kerger J., Groot Y., Wanders J., Verweij J., Wagener D. J. Phase 1 study of Carzelesin (U-80, 244) given (4-weekly) by intravenous bolus schedule. Br. J. Cancer, 79: 1454-1461, 1999.[CrossRef][Medline]
19. Delaloge S., Yovine A., Taamma A., Riofrio M., Brain E., Raymond E., Cottu P., Goldwasser F., Jimeno J., Misset J. L., Marty M., Cvitkovic E. Ecteinascidin-743: a marine-derived compound in advanced, pretreated sarcoma patients-preliminary evidence of activity. J. Clin. Oncol., 19: 1248-1255, 2001.[Abstract/Free Full Text]
20. PNU-166196A Investigator Brochure, Pharmacia & Upjohn. Document N 9950123, Version 2, 31 July, 2000.
21. Viallet J., Stewart D., Sheperd F., Ayoub J., Cormier Y., DiPietro N., Steward W. Tallimustine is inactive in patients with previously treated small cell lung cancer. A phase II trial of the National Cancer Institute of Canada Clinical Trials Group. Lung Cancer, 15: 367-373, 1996.[CrossRef][Medline]
22. Weiss G. R., Poggesi I., Rocchetti M., DeMaria D., Mooneyham T., Reilly D., Vitek L. V., Whaley F., Patricia E., Von Hoff D. D., O’Dwyer P. A phase I and pharmacokinetic study of tallimustine [PNU152241 (FCE 24517)] in patients with advanced cancer. Clin. Cancer Res., 4: 53-59, 1998.[Abstract]

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