A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies

Published on Jun 1, 2011in Cancer Chemotherapy and Pharmacology3.008
· DOI :10.1007/s00280-010-1410-1
Paula M. Fracasso25
Estimated H-index: 25
(UVA: University of Virginia),
Kerry J. Williams3
Estimated H-index: 3
(WashU: Washington University in St. Louis)
+ 23 AuthorsHelen Piwnica-Worms67
Estimated H-index: 67
(WashU: Washington University in St. Louis)
Purpose UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.
  • References (69)
  • Citations (43)
📖 Papers frequently viewed together
189 Citations
408 Citations
68 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
Background: The checkpoint kinases, Chk1 and Chk2 are Ser/Thr protein kinases, which function as key regulatory kinases in cellular DNA damage response pathways limiting cell-cycle progression in the presence of DNA damage. The development of checkpoint kinase inhibitors for the treatment of cancer has been a major objective in drug discovery over the past decade, as evidenced by three checkpoint kinase inhibitors entering clinic trials since late 2005. Objectives: This review describes and disc...
39 CitationsSource
#1Antonio Jimeno (Johns Hopkins University)H-Index: 55
#2Michelle A. Rudek (Johns Hopkins University)H-Index: 42
Last. Ross C. Donehower (Johns Hopkins University)H-Index: 67
view all 10 authors...
Purpose 7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine–threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan.
34 CitationsSource
#1Martin J. EdelmanH-Index: 19
#2Kenneth S. BauerH-Index: 18
Last. Janet DanceyH-Index: 45
view all 6 authors...
Purpose: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients and Methods: Patie...
36 CitationsSource
#1Aime A. Levesque (Dartmouth College)H-Index: 5
#2Alan Eastman (Dartmouth College)H-Index: 50
The tumor suppressor protein p53 plays a pivotal role in the DNA damage response and is defective in >50% of human tumors, which has generated substantial interest in developing p53-targeted cancer therapies. Various therapeutic rationales targeting p53 are currently under investigation including attempts to both activate and inhibit p53. Elevation of p53 can be achieved by either reintroducing an exogenous p53 gene or by blocking its association with its negative regulator hDM2. An alternate ap...
77 CitationsSource
#1Raymond P. Perez (Dartmouth College)H-Index: 26
#2Lionel D. Lewis (Dartmouth College)H-Index: 30
Last. Alan Eastman (Dartmouth College)H-Index: 50
view all 9 authors...
62 CitationsSource
#1Lisa A. Carey (UNC: University of North Carolina at Chapel Hill)H-Index: 61
#2Charles M. PerouH-Index: 130
Last. Robert C. Millikan (UNC: University of North Carolina at Chapel Hill)H-Index: 63
view all 17 authors...
ContextGene expression analysis has identified several breast cancer subtypes, including basal-like, human epidermal growth factor receptor-2 positive/estrogen receptor negative (HER2+/ER–), luminal A, and luminal B.ObjectivesTo determine population-based distributions and clinical associations for breast cancer subtypes.Design, Setting, and ParticipantsImmunohistochemical surrogates for each subtype were applied to 496 incident cases of invasive breast cancer from the Carolina Breast Cancer Stu...
2,541 CitationsSource
#1Deepa Sampath (University of Texas MD Anderson Cancer Center)H-Index: 16
#2Jorge E. Cortes (University of Texas MD Anderson Cancer Center)H-Index: 139
Last. William PlunkettH-Index: 79
view all 8 authors...
Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. S...
95 CitationsSource
#1Nicola F. SmithH-Index: 6
#2William D. FiggH-Index: 86
Last. Alex SparreboomH-Index: 68
view all 3 authors...
Abstract The anticancer agent irinotecan (CPT-11) is converted to SN-38, which is approximately 100 to 1000-fold more cytotoxic than the parent drug. The pharmacokinetics of irinotecan are extremely complex and have been the subject of intensive investigation in recent years. Irinotecan is subject to extensive metabolism by various polymorphic enzymes, including CES2 to form SN-38, members of the UGT1A subfamily, and CYP3A4 and CYP3A5, which form several pharmacologically inactive oxidation prod...
126 CitationsSource
#1Sebastien J. HotteH-Index: 22
#2Amit M. OzaH-Index: 54
Last. Hal W. HirteH-Index: 41
view all 9 authors...
Background: 7-Hydroxystaurosporine (UCN-01) inhibits serine-threonine kinases including the Ca 2+ and phospholipid-dependent protein kinase C (PKC), CDKs 2, 4, 6, Chk-1 and PDK1. UCN-01 mediates distinct effects in vitro/in vivo: cell cycle arrest in G 1 , abrogation of G 2 arrest by inhibiting chk1, induction of apoptosis and potentiation of cytotoxicity of S-phase-active chemotherapeutics including the topoisomerase 1 inhibitor topotecan (T). This phase I study was designed to determine the ma...
91 CitationsSource
#1Jill E. Kucab (UBC: University of British Columbia)H-Index: 6
#2Cathy Lee (UBC: University of British Columbia)H-Index: 7
Last. Sandra E. Dunn (UBC: University of British Columbia)H-Index: 39
view all 11 authors...
Introduction Phosphorylated Akt (P-Akt) is an attractive molecular target because it contributes to the development of breast cancer and confers resistance to conventional therapies. Akt also serves as a signalling intermediate for receptors such as human epidermal growth factor receptor (HER)-2, which is overexpressed in 30% of breast cancers; therefore, inhibitors to this pathway are being sought. New celecoxib analogues reportedly inhibit P-Akt in prostate cancer cells. We therefore examined ...
79 CitationsSource
Cited By43
#1Zhiqing Huang (Duke University)H-Index: 30
#2Eiji Kondoh (Kyoto University)H-Index: 13
Last. Susan K. Murphy (Duke University)H-Index: 48
view all 11 authors...
Objective: Ovarian cancer cells often exist in vivo as multicellular spheroids. Spheroid formation in vitro has been used to enrich for cancer stem cell populations from primary tumors. Such spheroids exhibit drug resistance and slow proliferation, suggesting involvement in disease recurrence. Our objectives were to characterize cancer spheroid phenotypes, determine gene expression profiles associated with spheroid forming capacity and to evaluate the responsiveness of spheroids to commonly used...
1 CitationsSource
#1Cui Liang (SJTU: Shanghai Jiao Tong University)H-Index: 2
#2Ming DingH-Index: 2
Last. Xun Cai (SJTU: Shanghai Jiao Tong University)H-Index: 3
view all 6 authors...
Abstract With the introduction of arsenic trioxide and all-trans retinoic acid, the prognosis of acute promyelocytic leukemia has greatly improved. However, all-trans retinoic acid resistance is still unresolved in acute promyelocytic leukemia relapsed patients. In this study, the clinical achievable concentration of 7-hydroxystaurosporine synergized with all-trans retinoic acid to induce terminal differentiation in all-trans retinoic acid resistant acute promyelocytic leukemia cell lines. Thoug...
1 CitationsSource
#1Yaqin Shi (NU: Nanjing University)H-Index: 1
#2Juan Jin (NU: Nanjing University)H-Index: 8
Last. Xiaoxiang Guan (Nanjing Medical University)H-Index: 16
view all 4 authors...
Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scar...
6 CitationsSource
#1Binita Das (UNMC: University of Nebraska Medical Center)H-Index: 4
#2Beth K. Neilsen (UNMC: University of Nebraska Medical Center)H-Index: 6
Last. Robert E. Lewis (UNMC: University of Nebraska Medical Center)H-Index: 31
view all 12 authors...
AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing ...
6 CitationsSource
#1Magnus T. Dillon (ICR: Institute of Cancer Research)H-Index: 7
#2Kevin J. Harrington (ICR: Institute of Cancer Research)H-Index: 70
ATR inhibitors are a new class of anti-cancer compounds reaching early phase clinical trials. They are predicted to have anti-cancer activity as monotherapy, and in combination with DNA damaging chemotherapies and ionizing radiation. We outline the clinical trials in progress using the current clinical candidates VX-970 (M6620) and AZD6738, discuss potential biomarkers for this class of drug and consider future avenues for development of ATR inhibitors.
#1Dekuang Zhao (University of Texas MD Anderson Cancer Center)H-Index: 11
#2William M. Tahaney (BCM: Baylor College of Medicine)H-Index: 2
Last. Powel H. Brown (BCM: Baylor College of Medicine)H-Index: 33
view all 5 authors...
The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with muta...
21 CitationsSource
#1Bowen Ke (Sichuan University)H-Index: 8
#2Mao Tian (Sichuan University)H-Index: 8
Last. Gu He (Sichuan University)H-Index: 24
view all 5 authors...
Evasion of cell death is one of the hallmarks of cancer cells, beginning with long-established apoptosis and extending to other new forms of cell death. An elaboration of cell death pathways thus will contribute to a better understanding of cancer pathogenesis and therapeutics. With the recent substantial biochemical and genetic explorations of cell death subroutines, their classification has switched from primarily morphological to more molecular definitions. According to their measurable bioch...
40 CitationsSource
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In respo...
60 CitationsSource
Chemotherapeutics used in cancer treatment may elicit pleiotropic effects interfering, for instance, directly on DNA metabolism or on endoplasmic organelles functions. Recently there has been a trend towards the use of molecular-targeted therapies as alternative treatments of cancer, arising from the need to overcome the onset of undesired side effects or drug-resistance. Thus, a major challenge is the design and synthesis of new agents able to interact with specific cellular components, often o...
24 CitationsSource
#1Gwenola ManicH-Index: 14
#2Florine Obrist (University of Paris-Sud)H-Index: 9
Last. Ilio Vitale (Sapienza University of Rome)H-Index: 18
view all 4 authors...
The ataxia telangiectasia mutated serine/threonine kinase (ATM)/checkpoint kinase 2 (CHEK2, best known as CHK2) and the ATM and Rad3-related serine/threonine kinase (ATR)/CHEK1 (best known as CHK1) cascades are the 2 major signaling pathways driving the DNA damage response (DDR), a network of processes crucial for the preservation of genomic stability that act as a barrier against tumorigenesis and tumor progression. Mutations and/or deletions of ATM and/or CHK2 are frequently found in tumors an...
56 CitationsSource