In vitro concurrent paclitaxel and radiation of four vulvar squamous cell carcinoma cell lines

Abstract

BACKGROUND.The antitubule agent paclitaxel causes a cell cycle blockage in the most radiosensitive part of the cell cycle, the GJM phase. The possible radiosensitizing effect of paclitaxel was tested in four vulvar (UM-SCV-lA, UM-SCV-lB, UM-SCV-2, and UM-SCV-4) squamous cell carcinoma (SCC) cell lines. METHODS. A 96-well plate clonogenic assay was performed with paclitaxel and radiation, both separately and concomitantly. Survival data were fitted to the linear quadratic model. The area under the curve, equivalent to the mean inactivation dose (D), was obtained by numerical integration. The effect of paclitaxel on radiosensitivity was measured as the AUC ratio (paclitaxel plus radiation: radiation alone). This ratio was compared with the surviving fraction (SF,) after paclitaxel alone. RESULTS. Paclitaxel concentrations of 0.4 to 2.0 nanomolar (nM) caused 1 to 70% inhibition of clonogenic survival. The AUC values of the cell lines were 1.9 to 2.9 gray. A full additive effect was observed when paclitaxel and radiation were administered concurrently; however, a supra-additive effect never occurred. The type of paclitaxel radiation interaction was not affected by the concentration of the drug nor did the type of interaction vary between cell lines studied. CONCLUSIONS. Paclitaxel and radiation used concomitantly produced a clear additive effect at all concentrations and in all Vulvar carcinoma cell lines tested. Although no supra-additive effect was observed, the additive effect already in nM concentrations could be beneficial in clinical use and, therefore, requires further investigation.

Paclitaxel combined with fractionated radiation in vitro: A study with vulvar squamous cell carcinoma cell lines

“…The effect of concomitant paclitaxel and radiation given in a single dose was clearly additive, as we have also shown earlier with 4 of the cell lines. 10 The paclitaxel sensitivity or intrinsic radiosensitivity did not affect the synergy; the effect of concomitant paclitaxel and radiation was of the same magnitude as the combined (Table III). The p-values were 0.000033, 0.000011 and 0.0022, respectively.…”

“…We had previously found an additive effect in 4 of these cell lines with paclitaxel and radiation given in a single dose. 10 We wanted to approach clinical conditions by dividing the radiation dose into 2 equal fractions given at 24 hr intervals. This was done to determine the SLDR capacity of the cell lines and to evaluate whether paclitaxel could enhance the growth-inhibitory effect of radiation, for example, by inhibiting the repair of SLD.…”

“…A stock solution of 100 nM was prepared in Ham's F-12 medium, kept at Ϫ18°C and thawed immediately before the experiments. We had previously tested the paclitaxel-sensitivities of vulvar SCC cell lines; 10,19 for the current study, we chose paclitaxel doses expected to cause 20% inhibition in clonogenic survival. Final dilutions of 0.45-1.2 nM were used in the experiments.…”

“…The results obtained with this combined treatment modality in vitro seem to be somewhat less than has been expected. Both supraadditive [3][4][5][6] and additive [7][8][9][10] results have been reported in a variety of malignant cell lines, but subadditive interaction has also been demonstrated in vitro. 11,12 Contradictory outcomes in cytotoxic studies on the mechanism of action of paclitaxel have thrown doubt on the accumulation in G 2 /M being the main reason for the antitumor activity of paclitaxel.…”

Cell Cycle–Dependent Antagonistic Interactions between Paclitaxel and γ-Radiation in Combination Therapy

“…The combination therapy of paclitaxel plus radiation is under extensive investigation on the rationale that paclitaxel is able to arrest cells at the G 2 -M phase, which is the most radiosensitive phase of the cell cycle (7-9). Previously, it was generally believed that paclitaxel might act cooperatively with radiation, serving as a radiosensitizer and resulting in supra-additive or even synergistic effects (11)(12)(13)(14)(15)19). However, the accumulating literature did not always support this hypothesis.…”