Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study

Hotte, S. J.; Oza, Amit M.; Winquist, Eric; Moore, Malcolm J.; Chen, E.X.; Brown, Shirley; Pond, Gregory R.; Dancey, Janet; Hirte, Hal W.

doi:10.1093/annonc/mdj076

Cited by 95 publications

(59 citation statements)

References 22 publications

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“…This schedule, which appears to be well tolerated, results in free, salivary UCN-01 plasma concentrations of 800 to 1,400 nmol/L, which are sustained for up to 3 weeks following drug administration. Combination of the new UCN-01 schedule with topotecan or cisplatin has shown preliminary evidence of patient activity (46,47). In our animal studies, the theoretical peak UCN-01 concentration for treatment of mammary tumors with the drug, based on instantaneous absorption of the entire agent, would be in the range of f300 nmol/L.…”

Section: Discussionmentioning

confidence: 85%

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

Hamed

Hawkins

Mitchell

et al. 2008

Molecular Cancer Therapeutics

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The present studies were initiated to determine in greater molecular detail how MEK1/2 inhibitors [PD184352 and AZD6244 (ARRY-142886)] interact with UCN-01 (7-hydroxystaurosporine) to kill mammary carcinoma cells in vitro and radiosensitize mammary tumors in vitro and in vivo and whether farnesyl transferase inhibitors interact with UCN-01 to kill mammary carcinoma cells in vitro and in vivo. Expression of constitutively activated MEK1 EE or molecular suppression of JNK and p38 pathway signaling blocked MEK1/2 inhibitor and UCN-01 lethality, effects dependent on the expression of BAX, BAK, and, to a lesser extent, BIM and BID. In vitro colony formation studies showed that UCN-01 interacted synergistically with the MEK1/2 inhibitors PD184352 or AZD6244 and the farnesyl transferase inhibitors FTI277 and R115,777 to kill human mammary carcinoma cells. Athymic mice carrying f100 mm 3 MDA-MB-231 cell tumors were subjected to a 2-day exposure of either vehicle, R115,777 (100 mg/kg), the MEK1/2 inhibitor PD184352 (25 mg/kg), UCN-01 (0.2 mg/kg), or either of the drugs in combination with UCN-01. Transient exposure of tumors to R115,777, PD184352, or UCN-01 did not significantly alter tumor growth rate or the mean tumor volume in vivo f15 to 30 days after drug administration. In contrast, combined treatment with R115,777 and UCN-01 or with PD184352 and UCN-01 significantly reduced tumor growth. Tumor cells isolated after combined drug exposure exhibited a significantly greater reduction in plating efficiency using ex vivo colony formation assays than tumor cells that were exposed to either drug individually. Irradiation of mammary tumors after drug treatment, but not before or during treatment, significantly enhanced the lethal effects of UCN-01 and MEK1/2 inhibitor treatment. These findings argue that UCN-01 and multiple inhibitors of the RAS-MEK pathway have the potential to suppress mammary tumor growth, and to interact with radiation, in vitro and in vivo.

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Section: Discussionmentioning

confidence: 85%

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

Hamed

Hawkins

Mitchell

et al. 2008

Molecular Cancer Therapeutics

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“…Chk1 inhibition is being pursued as a promising target for the treatment of cancer (Blagden and de Bono, 2005). The oldest of such drugs, UCN-01, has been in development for the longest period of time and is now in Phase II clinical trials (Hotte et al, 2006). However, phase I trials revealed certain disadvantages of this drug, including dose-limiting toxicities (Kortmansky et al, 2005) and extremely long half-life due to binding to a1-acid glycoprotein (Fuse et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53

Fishler

et al. 2010

Oncogene

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“…This therapeutic interest has led in recent years to the development of small molecules that selectively inhibit a particular component of the DNA damage response pathway, such as ATM, ATR, or the downstream cell cycle checkpoint kinases Chk1 and Chk2 (31). Chk1 has been of particular interest as a therapeutic target because its loss of function abrogates the G 2 cell cycle arrest and sensitizes even p53-deficient cancer cells to genotoxic agents, as best attested by studies with UCN-01, a known inhibitor that is currently in phase II clinical trials for patients with advanced cancers (14).…”

Section: Discussionmentioning

confidence: 99%

“…13) is a Chk1 inhibitor that abrogates the S-phase and G 2 -M checkpoints and potentiates the killing of cancer cells including those with p53 mutations by agents like cisplatin, camptothecin, and IR. Current phase II clinical trials in patients with advanced ovarian cancer, metastatic melanoma, large-cell lymphoma, and small-cell lung cancer will determine the clinical efficacy of UCN01 (14). The indocarbazole Go6976 is an effective inhibitor of Chk1 and Chk2 that abrogates the S and G 2 -M arrest and potentiates the cytotoxicity of a topoisomerase I inhibitor, but only in p53-defective cells (15).…”

Section: Introductionmentioning

confidence: 99%

Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2

Carlessi

Buscemi

Larson

et al. 2007

Molecular Cancer Therapeutics

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VRX0466617 is a novel selective small-molecule inhibitor for Chk2 discovered through a protein kinase screening program. In this study, we provide a detailed biochemical and cellular characterization of VRX0466617. We show that VRX0466617 blocks the enzymatic activity of recombinant Chk2, as well as the ionizing radiation (IR) -induced activation of Chk2 from cells pretreated with the compound, at doses between 5 and 10 Mmol/L. These doses of VRX0466617 inhibited, to some extent, the phosphorylation of Chk2 Ser 19 and Ser 33 -35 , but not of Chk2 Thr 68 , which is phosphorylated by the upstream ataxia-telangiectasia mutated (ATM) kinase. Interestingly, VRX0466617 induced the phosphorylation of Chk2 Thr 68 even in the absence of DNA damage, arising from the block of its enzymatic activity. VRX0466617 prevented the IR-induced Chk2-dependent degradation of Hdmx, concordant with the in vivo inhibition of Chk2. Analysis of ATM/ATM and Rad3-related substrates Smc1, p53, and Chk1 excluded a cross-inhibition of these kinases. VRX0466617 did not modify the cell cycle phase distribution, although it caused an increase in multinucleated cells. Whereas VRX0466617 attenuated IR-induced apoptosis, in short-term assays it did not affect the cytotoxicity by the anticancer drugs doxorubicin, Taxol, and cisplatin. These results underscore the specificity of VRX0466617 for Chk2, both in vitro and in vivo, and support the use of this compound as a biological probe to study the Chk2-dependent pathways. [Mol Cancer Ther 2007;6(3):935 -44]

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Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study

Abstract: DLT was observed at DL 3 and RPTD was determined to be DL 2. To date, this combination has been relatively well tolerated with some preliminary evidence of efficacy. A phase II study of this combination in patients with ovarian cancer is underway.

Cited by 95 publications

References 22 publications

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell deathin vitroandin vivo

Genetic instability and mammary tumor formation in mice carrying mammary-specific disruption of Chk1 and p53

Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2

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