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Enhancement of cisplatin and etoposide cytotoxicity after all‐trans retinoic‐acid‐induced cellular differentiation of a murine embryonal carcinoma cell line
Author(s) -
Guchelaar H.J.,
Uges D. R. A.,
TimmerBosscha H.,
De Vries E. G. E.,
Mulder N. H.,
DamMeiring A.,
Oosterhuis J. W.
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910550320
Subject(s) - etoposide , cisplatin , cell culture , embryonal carcinoma , retinoic acid , microbiology and biotechnology , cell cycle , cell , biology , cellular differentiation , cancer research , chemistry , chemotherapy , medicine , biochemistry , genetics , gene
The potential of a combination of differentiation induction and chemotherapy was analyzed. Treatment of the murine embryonal carcinoma (EC) cell line PCC 4 in vitro with all‐transretinoic acid (RA) was followed by exposure to cisplatin (CDDP) or etoposide (VP‐16). The expression of EC‐cell‐specific markers decreased upon 96 hr exposure to 10 −9 , 10 −8 , 10 −7 and 10 −6 M RA, indicating a loss of embryonal phenotype of the cells, whereas expression of markers specific for cytokeratins and neurofilaments was increased after this treatment. These data suggest early somatic differentiation of PCC 4 cells upon treatment with RA. Cellular growth rate of PCC 4 cells was not affected by preincubation with RA at 10 −9 M for 96 hr, but was reduced at 10 −8 and 10 −7 M RA and inhibited at 10 −6 M RA. Culture of PCC 4 cells in the presence of 10 −7 M RA for 96 hr led to accumulation in G 1 of the cell cycle, whereas at 10 −8 M RA cell‐cycle distribution was not affected. RA‐treated and ‐untreated PCC 4 cells were compared for CDDP and VP‐16 sensitivity. Pre‐treatment with 10 −9 , 10 −8 and 10 −7 M RA increased CDDP sensitivity, resulting in a 1.9‐, 2.7‐ and 2.6‐fold decrease in the concentrations inhibiting survival by 50% (IC 50 s) respectively. Pre‐treatment with 10 −8 and 10 −7 M RA increased VP‐16 sensitivity 2.5‐ and 3.0‐fold, respectively. Enhanced CDDP sensitivity at RA concentrations not affecting cell‐cycle distribution was not attributable to changes in cellular platinum (Pt) accumulation, or to changes of Pt‐DNA binding. Enhanced VP‐16 sensitivity also occurred while topoisomerase‐II activity was unchanged and topoisomerase‐I activity was increased 2‐fold. Furthermore, there was a 2.0‐ to 4.5‐fold increase in the cellular concentration of VP‐16 after 10 −8 and 10 −7 M RA pre‐treatment. In conclusion, this study shows that in PCC 4 cells the rationale for combining RA and VP‐16 or CDDP is 2‐fold: RA induces differentiation and increases CDDP and VP‐16 sensitivity.