The
platinum drug chemosensitivity of five human cervical
squamous cell carcinoma cell lines (HX/151, HX/155, HX/156, HX/160 and HX/171) derived from previously untreated patients has been determined. Compared to our data obtained previously using human ovarian
carcinoma cell lines, all five lines were relatively resistant to
cisplatin,
carboplatin,
iproplatin and
tetraplatin. One of the lines (HX/156) was exceptionally sensitive to the novel
platinum (IV) ammine/
amine dicarboxylates
JM216 [bis-acetatoammine dichloro (
cyclohexylamine)
platinum (IV)] and JM221 [ammine dibutyrato dichloro (
cyclohexylamine)
platinum (IV)]. The range in IC50 values across the five lines was approximately 2.5-fold for
cisplatin,
carboplatin and
iproplatin, 13-fold for
tetraplatin and
JM216, and 25-fold for JM221. No significant correlation (P > 0.05) was observed between
platinum drug chemosensitivity and either
glutathione levels or
cadmium chloride sensitivity, an
indicator of
metallothionein levels. In addition, there was no significant correlation (P > 0.05) between
cisplatin cytotoxicity and intracellular
cisplatin accumulation or
JM216 cytotoxicity and intracellular
JM216 accumulation over the dose range 5-100 microM (2 h exposure). The exceptional sensitivity of HX/156 to
JM216 appears, at least partially, to be a result of enhanced accumulation of
JM216. An 8.6-fold acquired
cisplatin resistant stable variant of HX/155 has been generated in vitro. Intracellular
cisplatin accumulation was reduced by 2.4 +/- 0.3-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure).
Glutathione levels in HX/155cisR were elevated by 1.3-fold in terms of
protein content and by 1.6-fold in terms of cell number. HX/155cisR was 1.9-fold resistant to
cadmium chloride. Total
platinum bound to
DNA after
cisplatin exposure (10, 25, 50 or 100 microM for 2 h) was 3.6 +/- 0.6-fold (mean +/- s.d.) lower in HX/155cisR. Hence the mechanism of acquired
cisplatin resistance in HX/155cisR appears to be multifocal, with reduced intracellular
drug accumulation and elevated
glutathione and
metallothionein levels combining to reduce
DNA platination levels. While HX/155cisR was cross-resistant to
tetraplatin and
carboplatin, novel
platinum (II) and (IV) ammine/
amine complexes, including
JM216 and JM221, partially circumvented resistance (resistance factors of 1.5-2). Non cross-resistance was observed to
iproplatin and nine non-
platinum anticancer agents. Intracellular
tetraplatin accumulation was reduced by 1.8 +/- 0.1-fold (mean +/- s.d.) in HX/155cisR across the dose range 1-100 microM (2 h exposure). In contrast, after
JM216 exposure (1-100 microM for 2 h), no significant difference in intracellular
platinum levels between HX/155 and HX/155cisR was observed.(ABSTRACT TRUNCATED AT 400 WORDS)