PMID- 12955040
OWN - NLM
STAT- MEDLINE
DCOM- 20040115
LR  - 20191107
IS  - 1340-6868 (Print)
IS  - 1340-6868 (Linking)
VI  - 10
IP  - 3
DP  - 2003
TI  - Combined antitumor activity of 7-hydroxystaurosporine (UCN-01) and tamoxifen 
      against human breast carcinoma in vitro and in vivo.
PG  - 260-7
AB  - BACKGROUND: 7-Hydroxystaurosporine (UCN-01) was originally isolated as a protein 
      kinase C inhibitor and has shown antitumor activity against several human cancer 
      cell lines. UCN-01 inhibits cell cycle progression from the G1 to the S phase and 
      is associated with inhibition of cyclin-dependent kinase (CDK) activity and 
      induction of intrinsic CDK inhibitor p21, leading to dephosphorylation of 
      retinoblastoma (Rb) protein. Tamoxifen (TAM) traps cancer cells in the G1 phase, 
      suggesting that the mechanism of action of TAM is similar to that of UCN-01. The 
      present study was conducted to assess the antitumor activity of UCN-01 combined 
      with TAM against human breast carcinoma cells in vitro and in vivo. MATERIALS AND 
      METHODS: MCF-7 cells were treated with UCN-01, TAM, or UCN-01 combined with TAM 
      at various concentrations in vitro. The antitumor effect was evaluated as the 
      inhibition rate (I.R.%) by MTT assay. Two human breast carcinoma xenografts in 
      nude mice, MCF-7 and Br-10, were treated with UCN-01, TAM or both agents 
      together. The expression of p21 and the phosphorylation status of Rb protein in 
      MCF-7 cells were detected by Western blotting. RESULTS: UCN-01 or TAM alone 
      inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. 
      Combined treatment with UCN-01 followed by TAM inhibited the growth of MCF-7 
      cells synergistically and no significant differences in cytotoxicity were 
      observed between the different sequences of UCN-01/TAM and TAM/UCN-01. 
      Combination treatment with UCN-01 and TAM against MCF-7 and Br-10 in vivo 
      exhibited superior antitumor effects compared with either agent treatment alone. 
      Although 0.1 microg UCN-01 per ml (I.R.: 48.1%) or 2 microM TAM (I.R.: 31%) 
      induced p21 expression, phosphorylation of Rb protein was not inhibited. However, 
      combination treatment with UCN-01 and TAM at the same concentrations resulted in 
      an I.R. of 67% and dephosphorylation of Rb protein. CONCLUSION: The present study 
      suggests that combining UCN-01 and TAM could result in augmented cytotoxicity 
      because of their similar mechanism of action. This combination may have potential 
      clinical applications for breast cancer treatment, by reducing the toxicity of 
      UCN-01.
FAU - Koh, Junichi
AU  - Koh J
AD  - Department of Surgery, Saitama Social Insurance Hospital, 4-9-3, Kitaurawa, 
      Saitama-shi, Saitama 330-0074, Japan. j-koh@jc4.so-net.ne.jp
FAU - Kubota, Tetsuro
AU  - Kubota T
FAU - Koyama, Toshiko
AU  - Koyama T
FAU - Migita, Tomofusa
AU  - Migita T
FAU - Hashimoto, Mitsumasa
AU  - Hashimoto M
FAU - Hosoda, Yoichiro
AU  - Hosoda Y
FAU - Kitajima, Masaki
AU  - Kitajima M
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - Breast Cancer
JT  - Breast cancer (Tokyo, Japan)
JID - 100888201
RN  - 0 (Antineoplastic Agents)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - 7BU5H4V94A (7-hydroxystaurosporine)
RN  - H88EPA0A3N (Staurosporine)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage/pharmacology
MH  - Blotting, Western
MH  - Breast Neoplasms/drug therapy
MH  - Cell Line, Tumor/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Staurosporine/*administration & dosage/*analogs & derivatives/pharmacology
MH  - Tamoxifen/*administration & dosage/pharmacology
EDAT- 2003/09/05 05:00
MHDA- 2004/01/16 05:00
CRDT- 2003/09/05 05:00
PHST- 2003/09/05 05:00 [pubmed]
PHST- 2004/01/16 05:00 [medline]
PHST- 2003/09/05 05:00 [entrez]
AID - 10.1007/BF02966727 [doi]
PST - ppublish
SO  - Breast Cancer. 2003;10(3):260-7. doi: 10.1007/BF02966727.