Selective cytotoxicity of gemcitabine on superficial malignant vs. normal human urothelial cells and the effects of hyperthermia — ASN Events
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Selective cytotoxicity of gemcitabine on superficial malignant vs. normal human urothelial cells and the effects of hyperthermia (#214)

Stefanie Farr 1 , Russ Chess-Williams 1 , Catherine McDermott 1
  1. Health Science and Medicine Faculty, Bond University, Gold Coast, QLD, Australia

Background:

Intravesical chemotherapy for bladder cancer limits systemic absorption but significant local urological side effects including dysuria and urgency of urination still occur. A newer agent, gemcitabine, has a favourable efficacy and toxicity profile in patients compared to other commonly used chemotherapies. Combined hyperthermia and chemotherapy has shown synergism in decreasing cell proliferation in bladder cancer cell lines and cancer recurrence in patients, however there are no reports on the effect of this therapy on the normal urothelial cells of the bladder.

Aim:

To investigate the toxicity of gemcitabine alone and in combination with hyperthermia in cultured human superficial bladder cancer cells with comparison to urothelial cells.

Methods:

The human urothelial bladder cancer cell lines RT4 and T24 and non-cancer UROtsa bladder cells in proliferative and differentiated forms were used in this study. Cells were treated with increasing doses of gemcitabine up to the maximal clinical concentration of 40mg/mL for 1 hour at either 37oC or 42oC. A resazurin viability assay was used to assess the effect of treatments on cell proliferation 72hours post treatment.

Results:

All cell lines displayed a reduction of cell survival with increasing concentrations of gemcitabine, assessed 72hrs post treatment. The potency of gemcitabine on cancer cells (LC50 of 0.32µM for RT4 and 0.4µM for T24 cells) was substantially greater than its potency on non-cancer cells (LC50 of 32.4mM for differentiated UROtsas and 6.6mM for proliferative UROtsas). Hyperthermia did not enhance the cytotoxicity of gemcitabine on the cancer cell lines RT4 and T24. The only synergy between hyperthermia and gemcitabine occurred in the differentiated UROtsa cells.

Conclusions:

Gemcitabine toxicity is selective to cancerous cells, showing an approximate 100,000-fold higher potency on the cancer cell lines RT4 and T24 relative to the differentiated urothelial cell line. This selectivity may explain the low incidence of urological adverse effects following intravesical administration with this agent.

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