|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology Randomized Phase I/II Study of Troxacitabine Combined With Cytarabine, Idarubicin, or Topotecan in Patients With Refractory Myeloid LeukemiasFrom the Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Division of Hematology, University of Southern California Keck Medical School; and Norris Cancer Center, Los Angeles, CA. Address reprint requests to Francis J. Giles, MD, The University of Texas, M.D. Anderson Cancer Center, Department of Leukemia, 1400 Holcombe Blvd., Box 428, Houston, TX 77030; email: frankgiles{at}aol.com.
Purpose: Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan. Patients and Methods: Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m2 by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 mg/m2/d IV over 2 hours on days 1 to 5, idarubicin 12 mg/m2 by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m2 as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination. Results: Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m2 once a day for 5 days and 1.0g/m2 once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m2 once a day for 5 days and 0.75 mg/m2 once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m2 once a day for 5 days and 9 mg/m2 once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase. Conclusion: Troxacitabine-based combinations had significant antileukemic activity.
ALL NATURALLY occurring nucleoside analogs and all nucleoside analogs currently approved as anticancer agents are in the D-configuration.1 Nucleoside L-enantiomers were relatively underdeveloped until recently, as they were considered to be unsuitable substrates for activating metabolic enzymes. The discovery of ß-L1, 3-oxathiolane cytosine (3TC, lamivudine) as a potent inhibitor of human immunodeficiency virus-1 reverse transcriptase led to acceptance that unnaturally configured nucleoside analogs could be metabolized by humans, which in turn led to the development of L-enantiomers as anticancer agents.2–5 Exchange of the sulfur endocyclic atom with an oxygen in the structure of lamivudine resulted in the formation of troxacitabine, which, unlike lamivudine, has broad-spectrum cytotoxic activity.1 In a phase I study in patients with refractory leukemia, troxacitabine was given as an intravenous (IV) infusion over 30 minutes daily for 5 days. The maximum tolerated dose (MTD) was defined as 8 mg/m2/d.6 Mucositis and hand-foot syndrome (HFS) were dose-limiting toxicities (DLTs), with skin rashes also observed as a significant toxicity. Three complete responses (CRs) and 1 partial remission (PR; 13%) were observed in 30 evaluable patients with acute myeloid leukemia (AML). One of five (20%) patients with refractory myelodysplastic syndromes (MDS) achieved a hematologic improvement (HI), and a patient with blastic phase of chronic myeloid leukemia (CML-BP) achieved a durable second chronic phase.6 A phase II study of troxacitabine given at the above MTD included a cohort of 42 patients with refractory AML, MDS, CML-BP, and acute lymphocytic leukemia (ALL).7 Confirming the phase I study observations, the significant toxicities observed were mucositis, HFS, and skin rash. In 16 assessable patients with AML, two CRs and one PR (18% overall response rate) were observed.7 Six (37%) of 16 assessable patients with CML-BP returned to chronic phase disease. Cytarabine (ara-C), idarubicin, and topotecan are often included in combination regimens for both previously untreated and relapsed patients with myeloid leukemias.8,9 A randomized phase I/II study was conducted to establish doses of troxacitabine given in combination with these agents. Additional patients were enrolled on study at potential phase II dose levels to make an initial assessment of efficacy.
Patient Eligibility Patients who had failed prior therapy for MDS refractory anemia with excess blasts (RAEB); RAEB in transformation (RAEB-T), chronic myelomonocytic leukemia (CMML), AML, or myeloid CML-BP were eligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance score of  2; serum bilirubin of 2.0 mg/dL; AST (serum glutamic-oxaloacetic transaminase) or ALT (serum glutamate pyruvate transaminase) levels less than three times the upper limit of normal (ULN) or less than five times the ULN if considered to be the result of leukemia; and serum creatinine 1.5 mg/dL. For the dose-finding portion of the study, patients with AML included either those receiving first salvage therapy with first CR duration less than 12 months or patients receiving second or subsequent salvage therapy. Once DLT for a combination was established, those patients with AML whose first CR duration was 12 months or greater were eligible. Patients with active controlled infection were eligible. All patients gave signed informed consent indicating that they were aware of the investigational nature of this study, in keeping with the policies of the M.D. Anderson Cancer Center and the University of Southern California Keck Medical School.
Treatment
Response and Toxicity Criteria CR in patients with AML or MDS was defined as normalization of the blood and bone marrow with 5% or fewer blasts, normocellular or hypercellular bone marrow, a granulocyte count above 109/L, and a platelet count above 100 x 109/L. Patients who met these criteria but had 6% to 25% marrow blasts were considered to have PR; hematologic improvement (HI) was defined as for CR, but with platelet counts remaining below 100 x 109/L. Other responses were considered as failures. For patients with CML-BP, return to chronic phase was considered a CR. Extramedullary CML-BP was considered a PR if the measurable disease was reduced by  50% and a CR if there was complete resolution of all measurable disease. Toxicity was graded on a scale of 0 to 5 using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 2.0 criteria.
The characteristics of the 87 patients (median age, 55 years; range, 2 to 83 years) treated on study are summarized in Table 2  . Sixty-eight (78%) patients had AML. Forty-one (60%) patients with AML were receiving a first salvage attempt: 33 after a first CR lasting less than 12 months (15 of whom had never achieved a CR, ie, had primary resistant disease), and eight with a first CR duration of greater than 12 months. Ten patients with AML were treated as second salvage, seven as third salvage, and 10 as fourth or subsequent salvage therapy. In total, 27 patients with AML had never achieved a prior remission before entry on study.
Toxicity All patients were evaluable for toxicity and received a total of 103 courses of treatment. Course one grade 3 and 4 nonhematologic toxicities by regimen and dose level are detailed in Table 3 . Across all regimens, skin rash was the most significant adverse event: eight (9%) patients had grade 3 toxicity; 33 (38%) patients had grade 2 toxicity. Four (5%) patients had grade 3 and 16 (18%) patients had grade 2 HFS. Six (7%) and 24 (28%) patients had grade 3 or grade 2 mucositis, respectively. One (1%) patient had grade 3 nausea and vomiting, headache, vertigo, bone pain, and constipation. This patient also experienced grade 4 hepatic transaminitis. A second patient had grade 3 hepatic transaminitis and hyperbilirubinemia. Both of these patients were treated at the +3 dose level of troxacitabine and ara-C, which was considered to be above the MTD for this combination. Three other patients had grade 3 hyperbilirubinemia (two treated at dose level 0 of troxacitabine and ara-C with oral steroids, and a third at the -1 dose level of troxacitabine and topotecan), which was felt to be potentially attributable to cytotoxic therapy. Three patients had grade 2 hyperbilirubinemia. Hyperbilirubinemia and/or hepatic transaminitis lasted a median of 7 days3–17 and were transient in all patients.
Fourteen (16%) patients had grade 2 nausea. One (1%) patient had grade 3 diarrhea, and fifteen patients (17%) had grade 2 diarrhea; this adverse event was equally frequent across all combinations. Other grade 2 toxicities included constipation in four patients, weakness in three patients, alopecia in three patients, fatigue in three patients, fever in two patients, bone pain in two patients, anorexia in two patients, myalgia in two patients, and in individual patients, arthralgia, gastrointestinal bleeding, hematuria, gastritis, conjunctivitis, coagulopathy, increase in transaminases, malaise, and edema. Six (7%) patients had fever of unknown origin at start of therapy, eight (9%) had controlled pneumonias diagnosed by chest radiograph documented at the start of therapy, one (1%) had controlled catheter-related infection, two had (2%) pneumonia and sepsis or other infection, and four (5%) had other infections. These patients were eligible for study therapy as the infections were considered to be controlled by antimicrobial therapy at the time of study entry. Twenty-four (28%) patients had either no febrile episodes on therapy or continuation of baseline-controlled infections. Sixty (69%) patients had a total of 90 infectious episodes during the first course of therapy. Thirty (35%) patients experienced fever of unknown origin during their first course of therapy. Twenty-five (29%) patients had bacteremias, and 20 (23%) had pneumonia diagnosed by either chest radiograph or computed tomographic scan. Nineteen (22%) patients had other infections, including vancomycin-resistant enterococci or Clostridium difficile in the stool. DLT were hepatic transaminitis, hyperbilirubinemia, and HFS syndrome on the troxacitabine and ara-C combination. The recommended phase II dose was 6 mg/m2 once a day for 5 days and 1.0g/m2 over 2 hours a day for 5 days, respectively. Both of the two patients who were initially randomly assigned to dose level 0 of this combination developed grade 3 skin rashes. As per protocol, three patients were then randomly assigned to therapy at the -1 dose level of the troxacitabine and ara-C combination. None of these patients developed grade 3 rashes or other DLTs. Brief courses of oral steroids had been shown to be effective therapy for troxacitabine-associated rashes on prior studies.6,7 Thus, three patients were then randomly assigned to receive dose level 0 of troxacitabine and ara-C with the addition of a 5-day schedule of oral prednisone, 30 mg daily, commencing the first day of chemotherapy. None of the initial three patients treated at this dose level developed grade 3 or 4 skin rash or other DLT. This dose level with oral steroids was then expanded to a total of 13 patients to further assess the risk of severe skin rash. One of these patients developed a grade 3 rash; none developed a grade 4 rash. DLTs were diarrhea, skin rash, and mucositis on the troxacitabine and topotecan combination. The recommended phase II dose was 4 mg/m2 once a day for 5 days and 0.75 mg/m2 once a day for 5 days, respectively. DLTs were HFS, skin rash, and mucositis on the troxacitabine and idarubicin combination. The recommended phase II dose was 4 mg/m2 once a day for 5 days and 9 mg/m2 once a day for 3 days, respectively.
Response
Of 11 evaluable patients with CML-BP, two obtained a clinical CR: one received troxacitabine and ara-C with resolution of extramedullary (pleural) blastic disease, the second received troxacitabine and idarubicin. The first responding patient was a 58-year-old male who initially developed CML-BP with pulmonary disease after a brief (1-month) chronic phase and received prior cyclophosphamide, ara-C, and topotecan (CAT) therapy. He responded to this therapy but relapsed after 1 year, with lung disease and thrombocythemia. He then received study therapy with troxacitabine and ara-C at the -1 dose level. The patient was lost to follow-up after one course of therapy. The second responding patient, a 40-year-old male, received troxacitabine and idarubicin at the -1 dose level as his first therapy for CML-BP. His CR lasted for 3 months on study, and the patient was then placed on maintenance imatinib mesylate therapy.15
Troxacitabine is a novel nucleoside L-enantiomer with significant cytotoxic activity.16,17 Troxacitabine undergoes phosphorylation to its mono-, di-, and triphosphate forms and is incorporated into DNA but not RNA.18 The triphosphate of troxacitabine is a substrate for both replicative and repair DNA polymerases.18 Troxacitabine is a complete DNA chain terminator, probably because the dioxolane ring of its structure lacks the necessary hydroxyl moiety for chain elongation. The cytotoxicity of troxacitabine against some tumor cell lines is directly correlated with the amount of its monophosphate present in DNA terminals.5 Chain excision of integrated troxacitabine monophosphate occurs slowly.19 Apurinic/apyrimidinic DNA endonuclease is the major enzyme in leukemia cells responsible for the removal of troxacitabine monophosphate from DNA.19 Deoxycytidine kinase (dCK), which lacks chiral specificity, catalyzes the monophosphorylation of both ara-C and troxacitabine.5,16 Deoxycytidine deaminase (dCD) is more chiral specific and cannot inactivate troxacitabine. The clinical import of changes over time in the levels or function of dCK and dCD in AML blasts, and specifically the effect of such changes on cellular resistance to ara-C, has been thoroughly but inconsistently described.20–23 Gourdeau et al24 have recently reported on the comparative in vivo antileukemic activity of troxacitabine and ara-C in human leukemia xenograft models with differing degrees of dCD activity. The antiproliferative activity of troxacitabine and ara-C was analyzed on hematopoietic cell lines by use of a thymidine incorporation assay using equitoxic schedules of both agents and evaluating their effect on the percentage increased life span. Initial data indicated that ara-C was ineffective in vivo against the HL60 promyelocytic leukemia cell line, whereas troxacitabine showed potent in vitro and in vivo activity in the same model. The authors postulated that the poor in vivo activity of ara-C against HL60 leukemia cells could be the result of the high dCD activity in this cell line. This hypothesis was tested in CCRF-CEM (T-lymphoblastoid leukemia) cells, which have undetectable levels of dCD activity.24 Ara-C was significantly more cytotoxic to the CCRF-CEM cell line than to the HL60 cell line, whereas troxacitabine was similarly active against both cell lines. In further studies, mice bearing CCRF-CEM tumor xenografts were treated with ara-C or troxacitabine, which were found to be comparable.24 These data indicate a potential for troxacitabine to have activity against tumors resistant to nucleoside analog therapy because of increased dCD levels.25–28 Troxacitabine has a unique pattern of cellular uptake and metabolism, which may also allow it to circumvent another mechanism of resistance to cytotoxic nucleoside analogs.29 Nucleoside-specific membrane transporters (NSMT) mediate plasma membrane permeation of many nucleoside analogs, including ara-C and fludarabine.30 In human prostate carcinoma DU-145, troxacitabine is transported rapidly into cells by both equilibrative-sensitive and equilibrative-insensitive nucleoside transport systems with subsequent accumulation of troxacitabine monophosphate, diphosphate, and triphosphate in a time- and concentration-dependent manner.5 Gati et al30 have reported that the cellular content NSMT in blasts from patients with AML and ALL correlate with the in vitro sensitivity to ara-C. As troxacitabine is not dependent on NSMT to achieve a lethal intracellular concentration, it may thus not be susceptible to NSMT-mediated mechanisms of resistance to ara-C. Gourdeau et al29 have compared the mechanisms of resistance with troxacitabine, gemcitabine, and ara-C in human leukemia and solid tumor cell lines. The parent CCRF-CEM leukemia cell line was highly sensitive to the antiproliferative effects of all three agents in contrast to a dCK-deficient variant, which was resistant to all three. An NSMT-deficient CCRF-CEM variant was very resistant to the cytotoxicity of either ara-C or gemcitabine while retaining sensitivity to troxacitabine, although at a modestly reduced level than the parent line. In a subsequent analysis of troxacitabine transportability by five NSMTs, its uptake was unaffected by the presence of NSMT inhibitors, indicating that the major route of cellular uptake of troxacitabine was passive diffusion.29 Unlike ara-C, which lacks proportionality between ara-C triphosphate formation and extracellular ara-C concentration, the formation of troxacitabine diphosphate increases linearly with increasing extracellular drug concentration.31 Troxacitabine does not inhibit ribonucleotide reductase and may thus be mechanistically complementary to several nucleosides that are cytotoxic in part via ribonucleotide reductase inhibition; for example, gemcitabine and 2'-deoxy-2'-(fluoromethylene)cytidine (FMdC).16 The pharmacokinetic behavior of troxacitabine is substantially different from that of other nucleoside analogs possessing a D- configuration, which are characterized by rapid disappearance from plasma because of deamination. In contrast, troxacitabine has a long terminal half-life (82 hours) and a systemic clearance comparable to the glomerular filtration rate (137 mL/min).6 Consistent with the latter observation, the majority of troxacitabine was excreted as unchanged drug in the urine (69%). In addition, troxacitabine concentrations of approximately 10 nmol/L were measurable on days 15 and 21 in some patients on the phase I study in patients with advanced leukemia.6 These concentrations are in the range of those shown to have growth-inhibitory activity in vitro in a variety of human normal and tumor cell lines (5 to 150 nmol/L). Thus, troxacitabine has a unique profile among nucleoside analogs in terms of its structure, pharmacokinetics, intracellular transport, and susceptibility to mechanisms of resistance. In this study, we defined the toxicity profiles of troxacitabine combinations. DLTs for both the topotecan and idarubicin combinations with troxacitabine were mucositis and skin rash, and these were also significant adverse events attributed to troxacitabine on phase I and II single-agent studies.6,7,32 The skin rashes were typically mildly to moderately pruritic, usually patchy rather than generalized, and resolved rapidly with a 3- to 5-day course of 20 to 30 mg of oral prednisone daily. The addition of prednisone to the troxacitabine and ara-C regimen also dramatically reduced the incidence of skin rash. The HFS seen on all three study regimens was usually more pronounced in the hands than in the feet, consisted of skin erythema and periarticular soft tissue swelling, was often associated with complaints of skin tightness or itching, lasted for 1 to 3 weeks, and ended with skin peeling. The signs and symptoms of HFS tend to take longer to resolve after the study combination regimens than was seen on the phase I or II leukemia studies, where a 3- to 5-day recovery period was typical.6,7 If future studies indicate that lower doses of troxacitabine are associated with less HFS, particularly in second or subsequent cycles, such lower doses may be worth exploring as maintenance or consolidation therapy in responding patients. Skin rashes were a DLT at level 0 doses of troxacitabine and ara-C given without oral steroids—both agents may cause skin rashes. With the addition of steroids, skin rashes were no longer dose limiting, which allowed increases in doses of both troxacitabine and ara-C. Hepatic transaminitis became a DLT at the +3 dose level of the troxacitabine and ara-C. Hepatic transaminitis and hyperbilirubinemia have not been a significant adverse event with troxacitabine given as a single agent.6,7,32 Liver dysfunction has been documented in patients receiving single-agent ara-C therapy at a range of doses and routes of administration.31,33–35 Hyperbilirubinemia was seen in one of 15 patients treated at the -1 level of troxacitabine and topotecan. Liver function abnormalities have been documented in patients receiving either single-agent idarubicin or topotecan.36,37 Elevations in serum bilirubin or hepatic transaminase levels are common among patients receiving therapy for refractory leukemia and are potentially attributable to multiple causes, including antileukemia therapy, antimicrobial agents, sepsis, or direct leukemic infiltration of the liver.38 Hepatic veno-occlusive disease, which occurred in two of six patients treated on a pilot study of a gemtuzumab ozogamicin (Mylotarg) and troxacitabine combination,39 was not observed on this study. In this study, we observed 10 CR and four HI in 74 evaluable patients with AML or MDS—an objective response rate of 19%. Two (18%) of 11 evaluable patients with CML-BP returned to chronic phase. The efficacy of all three study regimens was consistent with prior experience in that patients with relatively prolonged (> 52 week) CR1 durations had a significantly higher CR rate than those with brief or no prior CR. No obvious relationship existed between the amount or timing of prior ara-C exposure and likelihood of response to the combination. The primary purpose of this study was to establish phase II doses for each of the combinations. Although we also wished to make an initial assessment of efficacy, without randomized comparisons it is not feasible to attribute specific toxicities or efficacy individually to troxacitabine or its partner in each combination. In the United States, a multicenter study of troxacitabine and ara-C versus ara-C alone is being conducted in patients with refractory AML, and a prospective, randomized comparison of troxacitabine and ara-C, troxacitabine and idarubicin, and idarubicin and ara-C as therapy for patients aged 50 years or older with previously untreated adverse karyotype AML is currently ongoing at our institution. The initial and reduced doses of idarubicin and topotecan included in the study regimens were derived from current experience of these agents given in combination with ara-C.8 Alternate combinations with troxacitabine, examining different schedules of idarubicin or topotecan, may be worthy of investigation. The currently reported data on troxacitabine-based combinations would encourage the conduct of further studies of these regimens in patients with myeloid leukemias as CR was achieved with all three study regimens in patients with advanced refractory disease.
1. Mansour TS, Jin H, Wang W, et al: Anti-human immunodeficiency virus and anti-hepatitis-B virus activities and toxicities of the enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine and their 5-fluoro analogues in vitro. J Med Chem 38:1–4, 1995[CrossRef][Medline] 2. Balzarini J, Wedgwood O, Kruining J, et al: Anti-HIV and anti-HBV activity and resistance profile of 2', 3'-dideoxy- 3'-thiacytidine (3TC) and its arylphosphoramidate derivative CF 1109. Biochem Biophys Res Commun 225:363–369, 1996[CrossRef][Medline] 3. Mar EC, Chu CK, Lin JC: Some nucleoside analogs with anti-human immunodeficiency virus activity inhibit replication of Epstein-Barr virus. Antiviral Res 28:1–11, 1995[CrossRef][Medline]
4. Coates JA, Cammack N, Jenkinson HJ, et al: (-)-2'-deoxy-3'-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother 36:733–739, 1992
5. Grove KL, Cheng YC: Uptake and metabolism of the new anticancer compound beta-L-(-)- dioxolane-cytidine in human prostate carcinoma DU-145 cells. Cancer Res 56:4187–4191, 1996
6. Giles FJ, Cortes JE, Baker SD, et al: Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia. J Clin Oncol 19:762–771, 2001
7. Giles FJ, Garcia-Manero G, Cortes JE, et al: Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with refractory leukemia. J Clin Oncol 20:656–664, 2002
8. Estey EH, Thall PF, Cortes JE, et al: Comparison of idarubicin + ara-C-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 98:3575–3583, 2001
9. Beran M, Estey E, O’Brien S, et al: Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol 17:2819–2830, 1999 10. Beran M, Kantarjian H: Results of topotecan-based combination therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Semin Hematol 36:3–10, 1999[Medline] 11. Lee ST, Jang JH, Suh HC, et al: Idarubicin, cytarabine, and topotecan in patients with refractory or relapsed acute myelogenous leukemia and high-risk myelodysplastic syndrome. Am J Hematol 68:237–245, 2001[CrossRef][Medline] 12. Beran M, Estey E, O’Brien SM, et al: Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 31:521–531, 1998[Medline] 13. Beran M, Shen Y, Kantarjian H, et al: High-dose chemotherapy in high-risk myelodysplastic syndrome: Covariate-adjusted comparison of five regimens. Cancer 92:1999–2015, 2001[CrossRef][Medline]
14. Estey E, Kornblau S, Pierce S, et al: A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood 88:756, 1996
15. Kantarjian HM, Cortes J, O’Brien S, et al: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99:3547–3553, 2002
16. Grove KL, Guo X, Liu SH, et al: Anticancer activity of beta-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration. Cancer Res 55:3008–3011, 1995
17. Kadhim SA, Bowlin TL, Waud WR, et al: Potent antitumor activity of a novel nucleoside analogue, BCH-4556 (beta-L-dioxolane-cytidine), in human renal cell carcinoma xenograft tumor models. Cancer Res 57:4803–4810, 1997
18. Kukhanova M, Liu SH, Mozzherin D, et al: L- and D-enantiomers of 2', 3'-dideoxycytidine 5'-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity. J Biol Chem 270:23055–23059, 1995
19. Chou KM, Kukhanova M, Cheng YC: A novel action of human apurinic/apyrimidinic endonuclease: Excision of L-configuration deoxyribonucleoside analogs from the 3' termini of DNA. J Biol Chem 275:31009–31015, 2000 20. Chiba P, Tihan T, Szekeres T, et al: Concordant changes of pyrimidine metabolism in blasts of two cases of acute myeloid leukemia after repeated treatment with ara-C in vivo. Leukemia 4:761–765, 1990[Medline] 21. Hagenbeek A, Martens AC, Colly LP: In vivo development of cytosine arabinoside resistance in the BN acute myelocytic leukemia. Semin Oncol 14:202–206, 1987[Medline] 22. Harris AL, Grahame-Smith DG, Potter CG, et al: Cytosine arabinoside deamination in human leukaemic myeloblasts and resistance to cytosine arabinoside therapy. Clin Sci (Colch) 60:191–198, 1981[Medline] 23. Flasshove M, Frings W, Schroder JK, et al: Transfer of the cytidine deaminase cDNA into hematopoietic cells. Leuk Res 23:1047–1053, 1999[CrossRef][Medline] 24. Gourdeau H, Bibeau L, Ouellet F, et al: Comparative study of a novel nucleoside analogue (Troxatyl, troxacitabine, BCH-4556) and AraC against leukemic human tumor xenografts expressing high or low cytidine deaminase activity. Cancer Chemother Pharmacol 47:236–240, 2001[CrossRef][Medline] 25. van Haperen VW, Veerman G, Vermorken JB, et al: Regulation of phosphorylation of deoxycytidine and 2', 2'- difluorodeoxycytidine (gemcitabine); effects of cytidine 5'- triphosphate and uridine 5'-triphosphate in relation to chemosensitivity for 2', 2'-difluorodeoxycytidine. Biochem Pharmacol 51:911–918, 1996[CrossRef][Medline]
26. Weitman S, Marty J, Jolivet J, et al: The new dioxolane, (-)-2'-deoxy-3'-oxacytidine (BCH-4556, troxacitabine), has activity against pancreatic human tumor xenografts. Clin Cancer Res 6:1574–1578, 2000 27. Galmarini CM, Mackey JR, Dumontet C: Nucleoside analogues: Mechanisms of drug resistance and reversal strategies. Leukemia 15:875–890, 2001[CrossRef][Medline] 28. Gunzburg WH, Salmons B: Novel clinical strategies for the treatment of pancreatic carcinoma. Trends Mol Med 7:30–37, 2001[CrossRef][Medline]
29. Gourdeau H, Clarke ML, Ouellet F, et al: Mechanisms of uptake and resistance to troxacitabine, a novel deoxycytidine nucleoside analogue, in human leukemic and solid tumor cell lines. Cancer Res 61:7217–7224, 2001 30. Gati WP, Paterson AR, Belch AR, et al: Es nucleoside transporter content of acute leukemia cells: Role in cell sensitivity to cytarabine (araC). Leuk Lymphoma 32:45–54, 1998[Medline] 31. Grant S: Ara-C: cellular and molecular pharmacology. Adv Cancer Res 72:197–233, 1998[Medline]
32. de Bono JS, Stephenson J Jr, Baker SD, et al: Troxacitabine, an L-stereoisomeric nucleoside analog, on a five-times- daily schedule: A phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 20:96–109, 2002
33. Bodey GP, Coltman CA, Freireich EJ, et al: Chemotherapy of acute leukemia. Comparison of cytarabine alone and in combination with vincristine, prednisone, and cyclophosphamide. Arch Intern Med 133:260–266, 1974 34. Spriggs DR, Robbins G, Arthur K, et al: Prolonged high dose ARA-C infusions in acute leukemia. Leukemia 2:304–306, 1988[Medline] 35. Tanaka M, Kanamori H, Yamaji S, et al: Low-dose cytarabine-induced hepatic and renal dysfunction in a patient with myelodysplastic syndrome. Anticancer Drugs 10:289–291, 1999[CrossRef][Medline] 36. Carella AM, Berman E, Maraone MP, et al: Idarubicin in the treatment of acute leukemias. An overview of preclinical and clinical studies. Haematologica 75:159–169, 1990[Medline]
37. Ardizzoni A, Hansen H, Dombernowsky P, et al: Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: A phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 15:2090–2096, 1997 38. Giles F, Cortes J, Garcia-Manero G, et al: Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia. Invest New Drugs 19:13–20, 2001[CrossRef][Medline] 39. Giles FJ, Garcia-Manero G, O’Brien S, et al: Fatal hepatic venoocclusive disease on a phase I study of Mylotarg and Troxatyl in patients with refractory acute myeloid leukemia or myelodysplastic syndrome. Acta Haematol 108:164–167, 2002[CrossRef][Medline] Submitted April 2, 2002; accepted November 18, 2002.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
