The use of the anticancer agent vinorelbine (Navelbine) as a radiosensitizer to enhance the effectiveness of radiation treatment is suggested by a preclinical study reported at the annual meeting of the American Association of Cancer Research (AACR). Timing and cell cycle dependency appear to be two critical factors in producing the combination's effects.
In this preclinical study, vinorelbine appeared to be more effective when administered after radiation rather than prior to radiation. In addition, vinorelbine showed the most significant impact when irradiated cells were exposed to the drug after they had plateaued in the G2-M phase of the cell cycle.
The in vitro study evaluated the ability of vinorelbine to potentiate the effect of radiotherapy in the treatment of non-small-cell lung cancer (NSCLC) in the human cell line NCI-H460. Based on the results, researchers concluded that the combination merits clinical study.
"The purpose of this study was to determine if radiation...might be more effective when combined with Navelbine, considering the drug's efficacy in non-small-cell lung cancer," said David Duch, PhD, of Burroughs Wellcome Co., manufacturer of Navelbine. "We demonstrated that Navelbine may act as a potentiator of radiation and enhance radiation's role in blocking cell division."
When cells were exposed to vinorelbine for 24 hours and then irradiated at doses ranging from 1 to 8 Gy, the effect on the cells was dose-dependent. Radiation administered at 1 Gy combined with vinorelbine showed a 1.7-fold increase in blocking cell division over radiation alone; 6 Gy of radiation combined with vinorelbine had more than a 5-fold increase in blocking cell division over radiation alone.
The study also reversed the treatment sequence by administering radiation first and then exposing the cells to vinorelbine. Similar survival ratios were obtained at concentrations of vinorelbine that were 10-fold lower than those given prior to radiation.
"When we saw that Navelbine worked better after radiation, we examined its mechanism of action and determined that its effectiveness depended on what radiation had already done in the cell cycle in terms of blocking cell division," said Dr. Duch. "Cells treated with radiation become blocked in the G2-M phase of the cell cycle. We found that when we waited to add Navelbine until most of the treated cells were blocked at this stage, optimal potentiation was observed, and that Navelbine was not effective when administered prior to this time."
Radiation produced a maximum 60% to 70% block in the G2-M phase of the cell cycle after 10 hours. Vinorelbine given early after irradiation, when only 10% to 30% of the cells were in G2-M, produced cell survival ratios similar to the controls treated with radiation alone.