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10.1111/j.1349-7006.2001.tb01127.x

http://scihub22266oqcxt.onion/10.1111/j.1349-7006.2001.tb01127.x
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suck abstract from ncbi


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pmid11376563
      Jpn+J+Cancer+Res 2001 ; 92 (5 ): 537-45
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  • UCN-01 (7-hydoxystaurosporine) inhibits in vivo growth of human cancer cells through selective perturbation of G1 phase checkpoint machinery #MMPMID11376563
  • Abe S ; Kubota T ; Otani Y ; Furukawa T ; Watanabe M ; Kumai K ; Akiyama T ; Akinaga S ; Kitajima M
  • Jpn J Cancer Res 2001[May]; 92 (5 ): 537-45 PMID11376563 show ga
  • Mechanisms underlying tumor sensitivity to the antitumor agent UCN-01 (7-hydroxystaurosporine) were examined in the nude mouse model using three human tumor xenografts, two pancreatic cancers (PAN-3-JCK and CRL 1420) and a breast cancer (MX-1). UCN-01 antitumor activity was evaluated in terms of relative tumor weights in treated and untreated mice bearing the tumor xenografts. The activity of cyclin-dependent kinase 2 (CDK2), levels of p21 and p27 proteins, pRb status and cell cycle were evaluated. Induction of p21 and apoptosis were also assessed immunohistochemically in CRL 1420. UCN-01 was administered intraperitoneally at a dose of either 5 or 10 mg / kg daily for 5 days followed by a further 5 injections after an interval of 2 days. UCN-01 significantly suppressed the growth of both pancreatic cancers, but was ineffective against MX-1. p21 protein expression was markedly induced in the UCN-01-sensitive pancreatic carcinoma xenografts at both doses, but p21 induction was only evident in the UCN-01-resistant MX-1 at 10 mg / kg. MX-1 exhibited CDK2 activity that was 6-fold higher than that of pancreatic cancer strains, which may explain the resistance of MX-1 to UCN-01 despite the induction of p21 at the dose of 10 mg / kg. The UCN-01-sensitive tumors exhibited G1 arrest and increased levels of apoptosis, changes not observed in resistant MX-1. In conclusion, it appears that a determining factor of in vivo UCN-01 sensitivity involves the balance of CDK2 kinase activity and p21 protein induction, resulting in augmented pRb phosphorylation, G1 cell cycle arrest and apoptosis.
  • |*CDC2-CDC28 Kinases [MESH]
  • |Alkaloids/pharmacology/*therapeutic use [MESH]
  • |Animals [MESH]
  • |Antineoplastic Agents/pharmacology/*therapeutic use [MESH]
  • |Apoptosis/drug effects [MESH]
  • |Blotting, Western [MESH]
  • |Breast Neoplasms/drug therapy/metabolism/pathology [MESH]
  • |Cell Division/*drug effects [MESH]
  • |Cyclin-Dependent Kinase 2 [MESH]
  • |Cyclin-Dependent Kinase Inhibitor p21 [MESH]
  • |Cyclin-Dependent Kinases/metabolism [MESH]
  • |Cyclins/analysis/metabolism [MESH]
  • |DNA, Neoplasm/analysis [MESH]
  • |Drug Resistance, Neoplasm [MESH]
  • |G1 Phase/*drug effects [MESH]
  • |Humans [MESH]
  • |Immunohistochemistry [MESH]
  • |Male [MESH]
  • |Mice [MESH]
  • |Mice, Inbred BALB C [MESH]
  • |Mice, Nude [MESH]
  • |Neoplasm Transplantation [MESH]
  • |Neoplasms, Experimental/*drug therapy/metabolism/*pathology [MESH]
  • |Pancreatic Neoplasms/drug therapy/metabolism/pathology [MESH]
  • |Phosphorylation [MESH]
  • |Protein Serine-Threonine Kinases/metabolism [MESH]
  • |Retinoblastoma Protein/analysis/metabolism [MESH]
  • |Staurosporine/analogs & derivatives [MESH]


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