SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors

Panasci, L.; Stinson, Sherman F.; Melnychuk, David; Sandor, Victor; Miller, Wilson H.; Batist, Gerald; Patenaude, François; Bangash, N.; Panarello, Luca; Alaoui-Jamali, M.; Sausville, E. A.

doi:10.1200/jco.2003.03.047

Cited by 5 publications

(5 citation statements)

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“…Studies have shown the promising results of SarCNU in the treatment of brain tumors both in vitro and in vivo (Skalski et al, 1988; Marcantonio et al, 1997; Chen et al, 1999b). It has recently been tested for the cytotoxicity against a wide range of human cancer cell lines and used in the treatment of patients with advanced solid tumors (Chen et al, 1999a; Panasci et al, 2003).…”

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confidence: 99%

SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

Huynh

Chow

Chee

et al. 2005

Journal Cellular Physiology

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Hepatocellular carcinoma (HCC) is a major health problem in the Asia-Pacific region, with high incidence and mortality rate. There is currently no effective treatment for inoperable cases that represent the vast majority of patients. In the present study, we report that in vitro treatment of primary hepatoma, HepG2 (wild-type p53), PLC/PRF/5 (p53-mutant), and Hep3B (p53-deleted) cells with 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) resulted in upregulation of p53, p21(Cip1/Waf1), phosphorylated cdc-2 at Tyr15 in wild-type p53 cells and phosphorylation of cdc-2 at Tyr15 in p53-mutant or p53-deleted hepatoma cells. This was accompanied by the reduction in cdc-2 kinase activity and G(2)/M cell cycle arrest. These findings indicate that SarCNU-induced G(2)/M growth arrest in hepatoma cells by a p53-independent phosphorylation of cdc-2. Our data suggest the potential use of SarCNU in treatment of HCC.

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confidence: 99%

SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

Huynh

Chow

Chee

et al. 2005

Journal Cellular Physiology

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“…4,5,8 In recent years, this agent has been assessed for toxic activity against a wide range of human cancer cell lines, and it also has been used to treat patients with advanced solid tumors. 9,10 The progression of cells from G 2 to M phase is driven by activation of the Cdc-2-cyclin B1 complex within the nucleus. 11 The Cdc-2-cyclin B1 heterodimer induces mitosis by phosphorylating (and thereby activating) enzymes that regulate chromatin condensation, nuclear membrane breakdown, mitosis-specific microtubule reorganization, and actin cytoskeleton reorganization, with these regulatory effects making 'mitotic roundup' possible.…”

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confidence: 99%

2‐Chloroethyl‐3‐sarcosinamide‐1‐nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53‐dependent and p53‐independent pathways

Huynh

Nguyen

Panasci

et al. 2004

Cancer

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BACKGROUNDProstate carcinoma is the most commonly occurring malignancy in men. Although 2‐chloroethyl‐3‐sarcosinamide‐1‐nitrosourea (SarCNU), an analog of the chloroethylnitrosoureas, has been used in the treatment of advanced solid tumors, the molecular mechanisms underlying the antineoplastic activity of this agent are not well understood. In the current study, the authors sought to investigate the effects of SarCNU on prostate carcinoma cell growth in vivo and in vitro.METHODSMale SCID mice underwent subcutaneous implantation (on both flanks) of human CWR‐22 and CWR‐22R prostate carcinoma xenografts. Mice were treated with either vehicle or 60 or 80 mg SarCNU per kg body weight for 5 days, with tumor growth being assessed every 3 days. Animals were sacrificed 21 days after the final injection, and tumors subsequently were collected, weighed, and processed for analysis. Immunohistochemical analyses were performed to obtain data on the localization of p53 and p21Cip1/Waf1. Cell counting, terminal deoxynucleotidyltransferase–mediated deoxyuridine triphosphate nick end‐labeling (TUNEL) assays, cell cycle analyses, Western blotting, and in vitro kinase assays were performed to determine the effects of SarCNU on growth, apoptosis, cell cycle arrest, cell cycle–regulated protein levels, and Cdc‐2 activity, respectively.RESULTSSarCNU reduced tumor incidence and inhibited the growth of CWR‐22 and CWR‐22R xenografts. In addition, treatment with this agent led to increases in p21Cip1/Waf1 levels and p53 phosphorylation at Ser15. In vitro administration of SarCNU to cells with wild‐type p53 (LNCaP and primary CWR‐22 cells) and cells with mutant p53 (PC‐3 cells) resulted in G2/M arrest and the reduction of cellular Cdc‐2 activity. Up‐regulation of p53 levels, p53 phosphorylation at Ser15, and p21Cip1/Waf1 levels in primary CWR‐22 and LNCaP cells, as well as up‐regulation of Cdc‐2 phosphorylation at Tyr15 in PC‐3 cells, was detected.CONCLUSIONSSarCNU induced G2/M arrest in prostate carcinoma cells via p53‐dependent up‐regulation of p21Cip1/Waf1 and p53‐independent phosphorylation of Cdc‐2 at Tyr15. These findings suggest a potential role for SarCNU in the treatment of prostate malignancies. Cancer 2004. © 2004 American Cancer Society.

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“…Unfortunately, unexpectedly severe pulmonary toxicity, with DLCO fall in virtually all patients, led us to close this trial prematurely. This information was not predicted from the phase I study where only one episode of pulmonary toxicity was documented in 43 patients who had careful monitoring of lung function [12]. Five patients with glioma were entered in this phase I trial, the fatal pulmonary toxicity occurred in one of them.…”

Section: Discussionmentioning

confidence: 96%

“…No other patient on the phase I study showed evidence of pulmonary toxicity as measured by repeated DLCO and forced vital capacity determinations. The recommended dose for further evaluation was 860 mg/m 2 given orally on days 1, 5 and 9 every 42 days (6 weeks) [12].…”

Section: Introductionmentioning

confidence: 99%

Phase II Trial of SarCNU in Malignant Glioma: Unexpected Pulmonary Toxicity with a Novel Nitrosourea

et al. 2005

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SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors

Abstract: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.

Cited by 5 publications

References 9 publications

SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

2‐Chloroethyl‐3‐sarcosinamide‐1‐nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53‐dependent and p53‐independent pathways

Phase II Trial of SarCNU in Malignant Glioma: Unexpected Pulmonary Toxicity with a Novel Nitrosourea

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SarCNU, a Nitrosourea Analog on a Day 1, 5, and 9 Oral Schedule: A Phase I and Pharmacokinetic Study in Patients With Advanced Solid Tumors

Abstract: SarCNU was well tolerated and the MTD was 1,075 mg/m2. The recommended starting dose for phase II trials is 860 mg/m2 orally on days 1, 5, and 9 every 6 weeks.

Cited by 5 publications

References 9 publications

SarCNU‐induced G2/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

SarCNU‐induced G2/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

2‐Chloroethyl‐3‐sarcosinamide‐1‐nitrosourea (SarCNU) inhibits prostate carcinoma cell growth via p53‐dependent and p53‐independent pathways

Phase II Trial of SarCNU in Malignant Glioma: Unexpected Pulmonary Toxicity with a Novel Nitrosourea

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SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15

SarCNU‐induced G₂/M arrest in hepatoma cells is mediated by a p53‐independent phosphorylation of cdc‐2 at Tyr15