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Journal of Clinical Oncology, Vol 22, No 8 (April 15), 2004: pp. 1413-1419
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.07.111
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Phase I Trial of Tirapazamine and Cyclophosphamide in Children With Refractory Solid Tumors: A Pediatric Oncology Group Study

Victor M. Aquino, Steve D. Weitman, Naomi J. Winick, Susan Blaney, Wayne L. Furman, James L. Kepner, Peter Bonate, Mark Krailo, Wenchun Qu, Mark Bernstein

From the University of Texas Southwestern Medical Center at Dallas, Dallas; ILEX Oncology, San Antonio; Baylor College of Medicine, Houston, TX; St Jude’s Children’s Hospital, Memphis, TN; Keck School of Medicine, University of Southern California, Los Angeles; The Children’s Oncology Group, Arcadia, CA; and the University of Montreal, Montreal, Quebec, Canada

Address reprint requests to Victor M. Aquino, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-0612; e-mail: victor.aquino{at}utsouthwestern.edu and dcorreia{at}childrensoncologygroup.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors’ Disclosures of...
 REFERENCES
 
PURPOSE: To determine the dose limiting toxicity (DLT), maximum-tolerated dose (MTD), and pharmacokinetic profile of tirapazamine (Sanofi Synthelabo Research, Malvern, PA) combined with cyclophosphamide in children with recurrent solid tumors.

PATIENTS AND METHODS: Patients received a 2-hour infusion of tirapazamine, followed by 1,500 mg/m2 cyclophosphamide, and mesna once every 3 weeks. Dose escalation of tirapazamine began at 250 mg/m2 and was increased by 30% in subsequent cohorts. If DLT was hematologic, less-heavily pretreated patients were to be enrolled until their DLTs were encountered, and MTDs defined. Pharmacokinetic profiles were also characterized.

RESULTS: Twenty-three patients were enrolled onto the study. Pharmacokinetic data were calculated for 22 patients. Prolonged neutropenia was the DLT at 420 mg/m2 in heavily pretreated patients. Grade 3, reversible ototoxicity was the DLT in less-heavily pretreated patients at 420 mg/m2. Two (one with neuroblastoma and one with rhabdomyosarcoma) had partial responses. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had disease detectable in the bone marrow only and all evidence of bone marrow involvement resolved for 17 cycles of therapy. Four other patients had stable disease. An apparent dose-proportional increase in tirapazamine maximal concentration and area under the curvelast was observed. Tirapazamine clearance, volume of distribution at steady-state, and terminal half-life did not appear to be dose-dependent.

CONCLUSION: The recommended dose of tirapazamine given with 1,500 mg/m2 of cyclophosphamide once every 3 weeks is 325 mg/m2. Neutropenia and ototoxicity were dose-limiting. Based on early evidence of antitumor activity, additional studies appear warranted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors’ Disclosures of...
 REFERENCES
 
Surgery, radiation, and chemotherapy are the primary treatment modalities for pediatric solid tumors. One way to augment efficacy of conventional therapy is to capitalize on hypoxia that exists in solid tumors.1,2 Tirapazamine (1,2,3 benzotriazine-3-amine 1,4 dioxide; Sanofi Synthelabo Research, Malvern, PA) is bioreduced under hypoxic conditions to an active free radical species, which induces single- and double-strand breaks in DNA.3 It is more active in hypoxic, acidic environments,1,4-10 and its antitumor activity is supra-additive when combined with alkylating agents such as cisplatin3,11-13 and cyclophosphamide,14,15 and with radiation therapy.16-19

Phase I studies in adults with tirapazamine administered every 3 weeks as a single agent have been completed.20 Dose- limiting toxicity (DLT) in those studies was reversible muscle fatigue and cramping, and the maximum-tolerated dose (MTD) was 330 mg/m2.20 Tirapazamine has been studied with cisplatin in adult phase I studies and the DLT was ototoxicity at 390 mg/m2.21,22

Because of promising in vitro activity of tirapazamine and early data from adult trials,5,10,11,14,15,19-32 we conducted a phase I trial for children with refractory or recurrent solid tumors. Tirapazamine was combined with cyclophosphamide to avoid the ototoxicity encountered when combined with cisplatin. Our objectives were to establish the DLT and MTD of tirapazamine with cyclophosphamide given every 3 weeks to children with solid tumors that were refractory to conventional chemotherapy, to determine the pharmacokinetic profile of tirapazamine in children, and to document antitumor activity.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors’ Disclosures of...
 REFERENCES
 
Eligibility Criteria
Patients were eligible for enrollment if they were 21 years of age or younger and had histologically or cytologically documented diagnoses of solid tumors refractory to conventional chemotherapy or for which no effective therapy was known. Other eligibility criteria included life expectancy of 6 weeks or greater, adequate nutritional status, Karnofsky performance score of ≥ 50 (or Lansky play scale ≥ 50 in younger children), adequate bone marrow function (absolute neutrophil count ≥ 1,500/µL; platelet count ≥ 75,000/µL), and adequate hepatic and renal function (bilirubin level ≤ 1.5 mg/dL; ALT < five x upper limit of normal; normal serum creatinine for age or glomerular filtration rate ≥ 70 mL/min/1.73 m2). Patients were ineligible if they were receiving any other antineoplastic therapy, had not recovered from toxicities of previous chemotherapies, had severe, uncontrolled infections, or were pregnant or lactating. At enrollment, patients must have been 6 weeks from completion of extended radiation therapy.

After determining the MTD in this population (Stratum 1), the eligibility criteria were revised to study less-heavily pretreated patients (Stratum 2), and excluded those who had received more than two chemotherapy regimens, any central axis radiation (skull, spine, pelvis, or ribs), previous bone marrow or hematopoietic stem-cell transplant, or those with bone marrow involvement.

Informed consent was obtained from each patient or their legal guardian before enrollment in accordance with the National Cancer Institute (NCI; Bethesda, MD), individual institutional policies, and according to the Declaration of Helsinki.

Drug Administration and Study Design
Tirapazamine (IND46, 525, NSC130181) was synthesized by Sanofi Synthelabo Research (Malvern, PA) and supplied by the Division of Cancer Treatment, NCI, in 100-mL vials that contained 0.7 mg/mL of tirapazamine in an isotonic citrate buffer. Tirapazamine was drawn into a standard syringe and infused without diluent. The bottles were protected from light during administration.

In adult phase I studies, the MTD of tirapazamine when administered with cyclophosphamide was 320 mg/m2.33 Based on this data, the starting dose of tirapazamine we selected was 80% of the adult MTD or 250 mg/m2 per day given as a 2-hour infusion followed 2 hours later by 1,500 mg/m2 cyclophosphamide over 30 minutes. There was no dose escalation of cyclophosphamide. Patients received four total doses of mesna at 300 mg/m2/dose intravenously over 30 minutes (mixed with cyclophosphamide 3, 6, and 9 hours after the beginning of cyclophosphamide infusion). Treatment was repeated every 3 weeks in patients with complete or partial responses or stable disease. Dose escalation of tirapazamine was by 30% increments. No intrapatient dose escalation was permitted. A minimum of three assessable patients were treated at each dose level. If one of the first three patients entered at that dose level experienced a DLT during the first course, three more were entered at the same level. Toxicities were graded according to version 1 of the NCI Common Toxicity Criteria.34 DLT was defined as grade 4 neutropenia or thrombocytopenia of a 7-day or greater duration or as any grade 3 or 4 nonhematologic toxicity, with the exception of grade 3 nausea and vomiting, grade 3 fever, or grade 3 hepatic toxicity that returned to grade 1 before the next treatment course. In addition, any toxicity requiring a 2-week or longer additional delay before drug readministration (≥ 5 weeks from day 1) was considered dose-limiting.

The MTD of tirapazamine with cyclophosphamide was defined as the dose immediately below the level at which two or more patients of a cohort of six patients had DLT. Courses were repeated every 21 days in the absence of DLT. Patients with reversible DLT could receive additional cycles of therapy at one dose level below DLT if they had no progressive disease.

Before treatment each patient had a physical assessment including performance status, radiologic assessment of tumor size, laboratory measurements (complete blood count, standard biochemistries, and urinalysis), and audiograms or auditory-evoked responses. Neuro-ophthalmologic examinations in cooperative patients also were performed because of preclinical ocular toxicity in mice (though not in other species) and reports of visual disturbances in adults.5 During the study, CBCs were obtained two to three times per week. Physical examination, urinalysis, and limited biochemistry measurements were performed weekly. Audiograms or auditory-evoked potentials were measured at the end of each course. A neuro-ophthalmologic examination was performed after the first course only.

Pharmacokinetic, Pharmacodynamic, and Bioanalytical Methods
Blood samples for tirapazamine were collected from an antecubital vein in the opposite arm from the site of infusion at predose, at the midpoint of infusion, at the end of infusion, at 5, 10, 15, and 45 minutes, and at 1, 1.5, 2, 3, 4, and 6 hours after the end of infusion on day 1 of cycle 1. Concentrations of tirapazamine were assayed using a validated liquid chromatography with tandem mass spectrometry with a limit of quantification of 50 ng/mL under the direction of Sanofi-Synthelabo Research. Pharmacokinetic parameters were characterized using noncompartment methods.35 Area under the curve (AUC) was determined using the linear trapezoidal rule. All pharmacokinetic analyses were done using WINNonlin Pro (Version 4.0, Pharsight Corp, Mountain View, CA). Dose proportionality was examined by analysis of variance on log-transformed (to stabilize the variance) dose-normalized measures of exposure, AUC, and maximal concentration (Cmax). The relationship between ototoxicity and pharmacokinetic parameters (AUC and Cmax) was examined by logistic regression using SAS for Windows (Version 6, SAS Institute, Cary, NC).

Evaluation of Response
Patients with disease that could be measured radiographically were assessed for response to therapy. Tumor size was measured before the second and third cycles of treatment and after every other subsequent course until patients were removed from protocol therapy. Complete response was achieved when all evidence of disease disappeared, with no interval development of new lesions. Partial response was defined as 50% or greater decrease in the sum of products of the maximum perpendicular diameters of all measurable lesions, without progression in lesions or development of new lesions for at least 4 weeks. Minor response was defined as a greater than 25% but less than 50% reduction in the sum of the products of the maximum perpendicular diameters of all measured lesions without progression or new lesions for at least 4 weeks. Stable disease was defined as less than 25% reduction in the sum of products of the maximum perpendicular diameters of all measurable lesions without progression for at least 4 weeks. An increase of greater than 25% in the sum of products of the perpendicular diameters, or appearance of new lesions, was defined as progressive disease.

Statistical Considerations
Descriptive statistics of the tirapazamine plasma concentrations and pharmacokinetic parameters were calculated using WINNonlin Pro.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors’ Disclosures of...
 REFERENCES
 
Patients
Twenty-three patients were enrolled. Two were not assessable for toxicity. One received an incorrect dose of tirapazamine (too low), and one was not assessable for hematopoietic toxicity because CBCs were not measured. Characteristics for the 23 patients are summarized in Table 1. A median of two courses of tirapazamine and cyclophosphamide were administered (range, 1 to 14 courses).


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  		Table 1. Characteristics of 23 Patients Who Received Tirapazamine and Cyclophosphamide

 
Toxicity
Hematologic toxicity. Toxicities encountered are summarized in Table 2 and the grade 3 nonhematologic and grade 4 hematologic toxicities are summarized in Table 3. Myelosuppression was the DLT in heavily pretreated patients. Two of six at dose level 3 (tirapazamine dose 420 mg/m2) had dose-limiting neutropenia for at least 7 days. One patient had grade 4 anemia and two patients had grade 4 thrombocytopenia for 7 or more days, one at dose level 2 (tirapazamine dose 325 mg/m2) and one at dose level 3.


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  		Table 2. Number and Percentage of Courses With Grade 3 or 4 Toxicities According to Dose Level Assigned

 

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  		Table 3. Grade 3 Nonhematologic and Grade 4 Hematologic Toxicities in 21 Patients (assessable for toxicity) Who Received Tirapazamine and Cyclophosphamide

 
Nonhematologic toxicity. Myelosuppression was the DLT in Stratum 1 patients enrolled at dose level 3 (tirapazamine dose 420 mg/m2), so further accrual to that level was restricted to less-heavily pretreated patients. Two patients in that group had grade 3 ototoxicity with the first course of chemotherapy. Both patients reported complete hearing loss within 24 hours of receiving tirapazamine. Audiograms on both patients showed complete hearing loss across all frequencies. One of the children was diagnosed with Ewing’s sarcoma and the other with recurrent Wilms’ tumor. The second child had received cisplatin before enrollment; neither child had received CNS radiation. Both children had complete resolution within 1 week of presentation. Neither child received a second course of chemotherapy. Other toxicities encountered included one child with grade 3 hypoalbuminemia at dose level 2 (tirapazamine dose 325 mg/m2), and two with grade 2 myalgias at dose level 3 (tirapazamine dose 420 mg/m2). Grades 2 and 3 nausea and vomiting were seen at all dose levels. One patient developed a grade 2 rash at dose level 2, which was believed related to drug infusion.

Response
One with rhabdomyosarcoma had a partial response that lasted for 11 cycles at a dose of 325 mg/m2. One child with neuroblastoma had prolonged stable disease (10 cycles) at a dose of 250 mg/m2. This patient had neuroblastoma detectable in the bone marrow only and did not have disease considered measurable according to the definitions of the protocol. All evidence of bone marrow involvement by neuroblastoma in this patient resolved for 17 cycles of therapy. Four had stable disease lasting at least three cycles (two with neuroblastoma, one with rhabdomyosarcoma, and one with pinealoblastoma). All of the children who responded and three of the four with stable disease received cyclophosphamide as a part of prior chemotherapy.

Pharmacokinetic Data
Pharmacokinetic data were collected from 23 patients. Data from one patient (250 mg/m2) were excluded from pharmacokinetic analysis, as sample collection times were not recorded. Figure 1 shows mean tirapazamine concentration-time profile by dose. Figure 2 shows individual and mean pharmacokinetic parameters by dose. Table 4 presents the summary statistics for the pharmacokinetic parameters examined.



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  		Fig 1. Mean ± SD tirapazamine plasma concentrations on day 1 of the first cycle for each dose group. (A) Linear scale; (B) Semi-log scale. Error bars are standard deviations.

 


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  		Fig 2. Tirapazamine pharmacokinetic parameters on day 1 of the first cycle by dose group. (A) Maximal concentration; (B) area under the curve (AUC); (C) total systemic clearance; (D) volume of distribution; (E) total systemic clearance; (F) volume of distribution, steady state. Open circles are observed data, solid circles are mean value, and error bars are the standard deviations.

 

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  		Table 4. Mean ± SD Tirapazamine Pharmacokinetic Parameters on Day 1 of the First Cycle for Each Dose Group

 
Tirapazamine exposure showed dose proportionality over the range of doses examined. The median AUC (0-{infty}) was 12.1 µg x h/mL, 17.3 ug x h/mL, and 21.3 µg x h/mL for the 250, 325, and 420 mg/m2 groups, respectively. The percent of AUC (0-{infty}) extrapolated never exceeded 2% for any subject. Median maximal concentrations at the end of infusion were 5.6 µg/mL, 7.7 µg/mL, and 9.5 µg/mL for the 250, 325, and 420 mg/m2 dose groups, respectively. No difference in dose-normalized AUC or dose-normalized Cmax was observed between the dose groups.

After cessation of infusion, tirapazamine concentrations declined monophasically with a harmonic mean half-life of 0.7 hours (range, 0.4 to 1.0 hours). The median clearance was 20.8 L/h (range, 5.7 to 63.0 L/h) with a coefficient of variation (CV) of 60%. When clearance was standardized to body surface area (BSA), the median clearance was 19.6 L/h/m2 (range, 8.7 to 42.0 L/h/m2) with a CV of 32%. Tirapazamine was not extensively distributed, predominantly confined to extracellular fluid, showing a median volume of distribution at steady-state (Vdss) of 21.7 L (range, 2.0 to 70.2 L) with a CV of 69%. When Vdss was standardized to BSA, the median was 21.3 L/m2 (range, 3.1 to 46.5 L/m2) with a CV of 43%. For both clearance and Vdss, standardization by BSA reduced inter-patient variability.

Logistic regression failed to identify a relationship between ototoxicity and measures of exposure, such as maximal concentration, AUC(0-{infty}), and dose.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors’ Disclosures of...
 REFERENCES
 
Solid tumors contain areas of hypoperfusion caused by abnormal vasculature that lead to hypoxia, low pH, and nutritional deprivation, which might contribute to resistance to ionizing radiation and many antineoplastic drugs.2,36 This relative hypoxia can also be exploited for selective antineoplastic therapy with tirapazamine, which is active against hypoxic cells by an enzymatic reaction that adds an electron to the tirapazamine molecule, forming a highly reactive radical37 both in vitro and in vivo.16,18 The radical produces DNA damage that leads to chromosomal aberrations and eventual cell death.38 In the presence of oxygen, the radical is oxidized to the nontoxic parent compound.39 In preclinical models, synergistic antitumor activity was found with radiation, and many DNA-reactive drugs, including cyclophosphamide, cisplatin, nitrosureas, and melphalan.27 Tirapazamine has significant schedule-dependent synergy with cisplatin and induces DNA strand breaks through mechanisms that are independent of p53.3 A 1.6-fold increase in the time required for tumor cell growth occurred with concurrent treatment with tirapazamine compared with cisplatin alone.27 Major toxicities in adult trials with tirapazamine and cisplatin included muscle fatigue, cramping, and ototoxicity.40 In the current trial, we combined tirapazamine with cyclophosphamide based on preclinical14,15,41 and clinical data,33 which showed supra-additive activity with the two agents.

Pharmacokinetic studies were performed and the results were similar to those seen in adults.20 An apparent dose-proportional increase in tirapazamine Cmax and AUClast was observed. Tirapazamine plasma clearance, volume of distribution at steady-state, and apparent terminal half-life did not appear to be dependent on dose.

We evaluated the clinical toxicity of, and response to, tirapazamine combined with cyclophosphamide administered as a 2-hour infusion every 3 weeks to children with refractory solid tumors. In heavily pretreated patients, neutropenia was dose-limiting at a dose of 420 mg/m2. In less heavily pretreated patients, grade 3 reversible ototoxicity was dose-limiting at the same dose level. The MTD of tirapazamine when combined with 1,500 mg/m2 of cyclophosphamide was 325 mg/m2, similar to the MTD for tirapazamine seen in adults. Of note, most of the children who had responsive or stable disease had received prior cyclophosphamide containing chemotherapy. However, the responses seen in these patients may be as a result of the cyclophosphamide alone.

Although the main objective of this study was to find a safe dose combination of tirapazamine and cyclophosphamide in children, patients were also evaluated for response. One had a partial response (rhabdomyosarcoma, 11 cycles) and two had prolonged stable disease (neuroblastoma, 3 and 10 cycles). One patient without measurable disease had clearance of bone marrow involvement by neuroblastoma for 17 cycles.

In the current study, the MTD of tirapazamine when combined with 1,500 mg/m2 of cyclophosphamide was 325 mg/m2. A study is in progress evaluating the combination of tirapazamine with vincristine, doxorubicin, and cyclophosphamide in recurrent rhabdomyosarcoma.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors’ Disclosures of...
 REFERENCES
 
The appendix is included in the full-text version of this article, available on-line at http://www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.


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  		PARTICIPATING INVESTIGATORS - P9675

 

   Authors’ Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors’ Disclosures of...
REFERENCES
 
The authors indicated no potential conflicts of interest.


   Acknowledgment
 
We thank Sanofi Synthelabo Research, Malvern, PA, for performing the pharmacokinetic studies presented in this manuscript.


   NOTES
 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors’ Disclosures of...
 REFERENCES
 
1. Brown JM, Giaccia AJ: Tumour hypoxia: The picture has changed in the 1990s. Int J Radiat Biol 65:95-102, 1994[Medline]

2. Rockwell S: Use of hypoxia-directed drugs in the therapy of solid tumors. Semin Oncol 19:29-40, 1992 (4 suppl 11)

3. Wouters BG, Wang LH, Brown JM: Tirapazamine: A new drug producing tumor specific enhancement of platinum-based chemotherapy in non-small-cell lung cancer. Ann Oncol 10:S29-S33, 1999 (suppl 5)

4. Aboagye EO, Dillehay LE, Bhujwalla ZM, et al: Hypoxic cell cytotoxin tirapazamine induces acute changes in tumor energy metabolism and pH: A 31P magnetic resonance spectroscopy study. Radiat Oncol Investig 6:249-254, 1998[CrossRef][Medline]

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8. Shibata T, Shibamoto Y, Sasai K, et al: Tirapazamine: Hypoxic cytotoxicity and interaction with radiation as assessed by the micronucleus assay. Br J Cancer Suppl 27:S61-S64, 1996[Medline]

9. Skarsgard LD, Vinczan A, Skwarchuk MW, et al: The effect of low pH and hypoxia on the cytotoxic effects of SR4233 and mitomycin C in vitro. Int J Radiat Oncol Biol Phys 29:363-367, 1994[Medline]

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14. Dorie MJ, Brown JM: Modification of the antitumor activity of chemotherapeutic drugs by the hypoxic cytotoxic agent tirapazamine. Cancer Chemother Pharmacol 39:361-366, 1997[CrossRef][Medline]

15. Langmuir VK, Rooker JA, Osen M, et al: Synergistic interaction between tirapazamine and cyclophosphamide in human breast cancer xenografts. Cancer Res 54:2845-2847, 1994[Abstract/Free Full Text]

16. Herman TS, Teicher BA, Coleman CN: Interaction of SR-4233 with hyperthermia and radiation in the FSaIIC murine fibrosarcoma tumor system in vitro and in vivo. Cancer Res 50:5055-5059, 1990[Abstract/Free Full Text]

17. Shulman LN, Buswell L, Riese N, et al: Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors. Int J Radiat Oncol Biol Phys 44:349-353, 1999[CrossRef][Medline]

18. Zeman EM, Lemmon MJ, Brown JM: Aerobic radiosensitization by SR 4233 in vitro and in vivo. Int J Radiat Oncol Biol Phys 18:125-132, 1990[Medline]

19. Zhang M, Stevens G: Effect of radiation and tirapazamine (SR-4233) on three melanoma cell lines. Melanoma Res 8:510-515, 1998[Medline]

20. Senan S, Rampling R, Graham MA, et al: Phase I and pharmacokinetic study of tirapazamine (SR 4233) administered every three weeks. Clin Cancer Res 3:31-38, 1997[Abstract]

21. Johnson CA, Kilpatrick D, von Roemeling R, et al: Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. J Clin Oncol 15:773-780, 1997[Abstract/Free Full Text]

22. Aghajanian C, Brown C, O’flaherty C, et al: Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer. Gynecol Oncol 67:127-130, 1997[CrossRef][Medline]

23. Bedikian AY, Legha SS, Eton O, et al: Phase II trial of tirapazamine combined with cisplatin in chemotherapy of advanced malignant melanoma. Ann Oncol 8:363-367, 1997[Abstract/Free Full Text]

24. Bedikian AY, Legha SS, Eton O, et al: Phase II trial of escalated dose of tirapazamine combined with cisplatin in advanced malignant melanoma. Anticancer Drugs 10:735-739, 1999[Medline]

25. Del Rowe J, Scott C, Werner-Wasik M, et al: Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme. J Clin Oncol 18:1254-1259, 2000[Abstract/Free Full Text]

26. Dorie MJ, Brown JM: Tumor-specific, schedule-dependent interaction between tirapazamine (SR 4233) and cisplatin. Cancer Res 53:4633-4636, 1993[Abstract/Free Full Text]

27. Holden SA, Teicher BA, Ara G, et al: Enhancement of alkylating agent activity by SR4233 in the FSaIIc murine fibrosarcoma. J Natl Cancer Inst 84:187-193, 1992[Abstract/Free Full Text]

28. Jones GD, Weinfeld M: Dual action of tirapazamine in the induction of DNA strand breaks. Cancer Res 56:1584-1590, 1996[Abstract/Free Full Text]

29. Lartigau E, Guichard M: The effect of tirapazamine (SR-4233) alone or combined with chemotherapeutic agents on xenografted human tumours. Br J Cancer 73:1480-1485, 1996[Medline]

30. Lee DJ, Trotti A, Spencer S, et al: Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: A Phase II study. Int J Radiat Oncol Biol Phys 42:811-815, 1998[CrossRef][Medline]

31. Siim BG, van Zijl PL, Brown JM: Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro. Br J Cancer 73:952-960, 1996[Medline]

32. Siim BG, Menke DR, Dorie MJ, et al: Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: Relationship to tumor hypoxia. Cancer Res 57:2922-2928, 1997[Abstract/Free Full Text]

33. Pazdur R, Diaz-Canton E, Reddy S, et al: Phase I study of intravenously administered tirapazamine (WIN 59075) plus cyclophosphamide. Ann Oncol 7:98, 1996 (suppl 1)

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35. Cawello W, Antonucci T: The correlation between pharmacodynamics and pharmacokinetics: Basics of pharmacokinetics-pharmacodynamics modeling. J Clin Pharmacol 37:65S-69S, 1997 (suppl 1)[Free Full Text]

36. Brown JM, Giaccia AJ: The unique physiology of solid tumors: Opportunities (and problems) for cancer therapy. Cancer Res 58:1408-1416, 1998[Abstract/Free Full Text]

37. Brown JM: SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours. Br J Cancer 67:1163-1170, 1993[Medline]

38. Wang J, Biedermann KA, Brown JM: Repair of DNA and chromosome breaks in cells exposed to SR 4233 under hypoxia or to ionizing radiation. Cancer Res 52:4473-4477, 1992[Abstract/Free Full Text]

39. Lloyd RV, Duling DR, Rumyantseva GV, et al: Micrsomal reduction of 3-amino-1,2,4-benzotriazine-1,4-dioxide to a free radical. Mol Pharmacol 40:440-445, 1991[Abstract]

40. Doherty N, Hancock SL, Kaye S, et al: Muscle cramping in phase I clinical trials of tirapazamine (SR 4233) with and without radiation. Int J Radiat Oncol Biol Phys 29:379-382, 1994[Medline]

41. Masunaga SI, Ono K, Suzuki M, et al: Usefulness of tirapazamine as a combined agent in chemoradiation and thermo-chemoradiation therapy at mild temperatures: Reference to the effect on intratumor quiescent cells. Jpn J Cancer Res 91:566-572, 2000[CrossRef][Medline]

Submitted July 18, 2003; accepted February 3, 2004.


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