The role of p53 in the chemotherapeutic responses to cisplatin, doxorubicin and 5-fluorouracil treatment.
A panel of tumour models used extensively for in vivo evaluation of new drugs was characterised for their p53 status. Basal p53 protein levels were measured by immunodetection on both formalin-fixed tumour tissue and from protein extracts of fresh tumours. High levels of nuclear-specific staining, indicative of p53 mutation, was seen in 15/25 tumours, with the remainder showing intermittent or no staining. The functional status of p53 cDNA from these tumours was assayed within the functional analysis of separated alleles in yeast (F.A.S.A.Y.) reporter system. The cDNA from those tumours with high levels of p53 protein showed 14/15 failing to activate the reporter gene. The cDNA from tumours with low or non-detectable p53 levels showed 8/10 with wild-type p53. Tumours were grown subcutaneously in mice (n=10). Each mouse was given maximum tolerated doses for either doxorubicin, 5-fluorouracil or cisplatin. Tumour volumes were measured daily, alongside untreated controls. The specific growth delay values for each tumour were separated into two groups, those with functional p53 (wild-type) and those without (mutant and null status). The Mann-Whitney U test was performed on the groups of data, to evaluate differences in their response on the basis of p53 status. Cisplatin was moderately active against tumours with wild-type and mutant p53 genes with no significant difference seen between both groups. However, a significant difference in specific growth delay was seen between the two groups when treated with doxorubicin or 5-fluorouracil (P=0.05), indicating a role for p53 protein in modulating the in vivo efficacy of these agents.
Dart
D Alwyn
DA
Cancer Research Unit, University of Bradford, Bradford BD7 1DP, UK.
Picksley
Steven M
SM
Cooper
Patricia A
PA
Double
John A
JA
Bibby
Michael C
MC
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D002945:Cisplatin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil