PMID- 10732766
OWN - NLM
STAT- MEDLINE
DCOM- 20000405
LR  - 20220408
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 82
IP  - 4
DP  - 2000 Feb
TI  - Sensitivity to CPT-11 of xenografted human colorectal cancers as a function of 
      microsatellite instability and p53 status.
PG  - 913-23
AB  - Biological parameters influencing the response of human colorectal cancers (CRCs) 
      to CPT-11, a topoisomerase 1 (top1) inhibitor, were investigated using a panel of 
      nine CRCs xenografted into nude mice. CRC xenografts differed in their p53 status 
      (wt or muf) and in their microsatellite instability phenotype (MSI+ when 
      altered). Five CRC xenografts were established from clinical samples. All five 
      had a functional p53, two were MSI+ and three were MSI-. Tumour-bearing nude mice 
      were treated intraperitonealy (i.p.) with CPT-11. At 10 mg kg(-1) of CPT-11, four 
      injections at 4-day intervals, four of the five xenografts responded to CPT-11 
      (growth delay of up to 10 days); the non-responder tumour was MSI-. At 40 mg 
      kg(-1) of CPT-11, six injections at 4-day intervals, the five CRCs displayed 
      variable but marked responses with complete regressions. In order to assess the 
      role of p53 status in CPT-11 response, four CRC lines were used. HT29 cell line 
      was MSI-/Ala273-mutp53, its subclone HT29A3 being transfected by wtp53. LoVo cell 
      line was MSI+/wtp53, its subclone X17LoVo dominantly expressed Ala273-mutp53 
      after transfection. LoVo tumours (MSI+/mutp53) were more sensitive than X17LoVo 
      (MSI+/mutp53. HT 29 tumours (MSI-Imutp53), were refractory to CPT-11 while HT29A3 
      tumours (MSI-/wtp53) were sensitive, showing that wtp53 improves the 
      drug-response in these MSI- tumours. Levels of mRNA expression of top1, fasR, 
      TP53 and mdr1 were semi-quantified by reverse transcription polymerase chain 
      reaction. None of these parameters correlated with CPT-11 response. Taken 
      together, these observations indicate that MSI and p53 alterations could be 
      associated with different CPT-11 sensitivities; MSI phenotype moderately 
      influences the CPT-11 sensitivity, MSI+ being more sensitive than MSI(-)CRC 
      freshly obtained from patients, mutp53 status being associated with a poor 
      response to CPT-11.
FAU - Bras-Goncalves, R A
AU  - Bras-Goncalves RA
AD  - Institut Curie, UMR 147 CNRS-Institut Curie, Paris, France.
FAU - Rosty, C
AU  - Rosty C
FAU - Laurent-Puig, P
AU  - Laurent-Puig P
FAU - Soulie, P
AU  - Soulie P
FAU - Dutrillaux, B
AU  - Dutrillaux B
FAU - Poupon, M F
AU  - Poupon MF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (DNA Primers)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 7673326042 (Irinotecan)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/*pharmacology
MH  - Base Sequence
MH  - Camptothecin/*analogs & derivatives/pharmacology
MH  - Cell Division/drug effects
MH  - Colorectal Neoplasms/genetics/*pathology
MH  - DNA Primers
MH  - Female
MH  - Humans
MH  - Irinotecan
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Microsatellite Repeats/*genetics
MH  - Mutation
MH  - Phenotype
MH  - Tumor Suppressor Protein p53/*genetics
PMC - PMC2374412
EDAT- 2000/03/25 00:00
MHDA- 2000/03/25 00:01
CRDT- 2000/03/25 00:00
PHST- 2000/03/25 00:00 [pubmed]
PHST- 2000/03/25 00:01 [medline]
PHST- 2000/03/25 00:00 [entrez]
AID - S0007092099910194 [pii]
AID - 10.1054/bjoc.1999.1019 [doi]
PST - ppublish
SO  - Br J Cancer. 2000 Feb;82(4):913-23. doi: 10.1054/bjoc.1999.1019.