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2001 ; 92
(5
): 537-45
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
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]