Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo

Abstract

Chemotherapy for lung cancer not only has severe side effects but frequently also exhibits limited, if any clinical effectiveness. Dexamethasone (DEX) and similar glucocorticoids (GCs) such as prednisone are often used in the clinical setting, for example, as cotreatment to prevent nausea and other symptoms. Clinical trials evaluating the impact of GCs on tumour control and patient survival of lung carcinoma have never been performed. Therefore, we isolated cancer cells from resected lung tumour specimens and treated them with cisplatin in the presence or absence of DEX. Cell number of viable and dead cells was evaluated by trypan blue exclusion and viability was measured by the MTT-assay. We found that DEX induced resistance toward cisplatin in all of 10 examined tumour samples. Similar results were found using gemcitabine as cytotoxic drug. Survival of drug-treated lung carcinoma cells in the presence of DEX was longlasting as examined 2 and 3 weeks after cisplatin treatment of a lung carcinoma cell line. These data corroborate recent in vitro and in vivo xenograft findings and rise additional concerns about the widespread combined use of DEX with antineoplastic drugs in the clinical management of patients with lung cancer.

Figure 1

DEX promotes cisplatin- and gemcitabine-inhibited viability of fresh lung carcinoma sample. Tumour cells from (A) five adenocarcinomas (B, C) four squamous cell carcinomas and (D) one small cell carcinoma were isolated and were cultivated in a concentration of 5 × 10⁵ ml⁻¹ in the absence (white bars) or presence of DEX (0.1, 1 or 10 μM as indicated) for 24 h. Thereafter, cisplatin or gemcitabine were added in concentrations indicated or not (CO) and viability was measured by the MTT-assay after additional 48 h. Eight wells per treatment were analysed and s.d. were less than 10%.

Figure 2

DEX promotes proliferation and inhibits drug-induced death of fresh lung carcinoma samples. (A) Freshly isolated tumour cells from patient 3 and 9 were cultivated in a concentration of 5 × 10⁵ ml⁻¹ in the absence or presence of DEX (1 μM) for 48 h as indicated. Cisplatin (CIS, 17 μM) was added or not as indicated and viable or dead cells were counted by trypan blue exclusion 2, 4 or 6 days (d) later. s.d. are shown and were less than 10%. (B) P693 lung carcinoma cells were treated as described above and cells were photographed 2 and 3 weeks later.