Abstract:
Cisplatin produces good responses in solid tumours
including small cell lung cancer (SCLC) but this is
limited by the development of resistance. Oxaliplatin is
reported to show activity against some cisplatin-resistant
cancers but there is little known about oxaliplatin in
SCLC and there are no reports of oxaliplatin resistant
SCLC cell lines. Studies of drug resistance mainly focus
on the cellular resistance mechanisms rather than how
the cells develop resistance. This study examines the
development of cisplatin and oxaliplatin resistance in
H69 human SCLC cells in response to repeated treatment
with clinically relevant doses of cisplatin or oxaliplatin
for either 4 days or 2 h. Treatments with 200 ng/
ml cisplatin or 400 ng/ml oxaliplatin for 4 days produced
sublines (H69CIS200 and H690X400, respectively)
that showed low level (approximately two-fold)
resistance after eight treatments. Treatments with
1,000 ng/ml cisplatin or 2,000 ng/rnl oxaliplatin for 2 h
also produced sublines, however, these were not stably
resistant suggesting shorter treatment pulses of drug
may be more effective. Cells survived the first five
treatments without any increase in resistance, by
arresting their growth for a period and then regrowing.
The period of growth arrest was reduced after the sixth
treatment and the H69CIS200 and H690X400 sublines
showed a reduced growth arrest in response to cisplatin
and oxaliplatin treatment suggesting that 'regrowth
resistance' initially protected against drug treatment and
this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose
escalation produced more surviving sublines than cisplatin
dose escalation but neither set of sublines were
associated with increased resistance as determined by 5-
day cytotoxicity assays, also suggesting the involvement
of regrowth resistance. The resistant sublines showed no
change in platinum accumulation or glutathione levels
even though the H690X400 subline was more sensitive
to buthionine sulphoximine treatment. The H69CIS200
cells were cross-resistant to oxaliplatin demonstrating
that oxaliplatin does not have activity against low level
cisplatin resistance. Relative to the H69 cells, the
H69CIS200 and H690X400 sublines were more sensitive
to paclitaxel and taxotere suggesting that the taxanes
may be useful in the treatment of platinum-resistant
SCLC. These novel cellular models of cisplatin and oxaliplatin
resistant SCLC will be useful in developing
strategies to treat platinum-resistant SCLC.
