Navelbine Promising as a Radiosensitizer in Non-Small-Cell Lung Cancer

The use of the anticancer agent vinorelbine (Navelbine) as a radiosensitizerto enhance the effectiveness of radiation treatment is suggestedby a preclinical study reported at the annual meeting of the AmericanAssociation of Cancer Research (AACR). Timing and cell cycle dependencyappear to be two critical factors in producing the combination'seffects.

In this preclinical study, vinorelbine appeared to be more effectivewhen administered after radiation rather than prior to radiation.In addition, vinorelbine showed the most significant impact whenirradiated cells were exposed to the drug after they had plateauedin the G2-M phase of the cell cycle.

The in vitro study evaluated the ability of vinorelbine to potentiatethe effect of radiotherapy in the treatment of non-small-celllung cancer (NSCLC) in the human cell line NCI-H460. Based onthe results, researchers concluded that the combination meritsclinical study.

"The purpose of this study was to determine if radiation...mightbe more effective when combined with Navelbine, considering thedrug's efficacy in non-small-cell lung cancer," said DavidDuch, PhD, of Burroughs Wellcome Co., manufacturer of Navelbine."We demonstrated that Navelbine may act as a potentiatorof radiation and enhance radiation's role in blocking cell division."

When cells were exposed to vinorelbine for 24 hours and then irradiatedat doses ranging from 1 to 8 Gy, the effect on the cells was dose-dependent.Radiation administered at 1 Gy combined with vinorelbine showeda 1.7-fold increase in blocking cell division over radiation alone;6 Gy of radiation combined with vinorelbine had more than a 5-foldincrease in blocking cell division over radiation alone.

The study also reversed the treatment sequence by administeringradiation first and then exposing the cells to vinorelbine. Similarsurvival ratios were obtained at concentrations of vinorelbinethat 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 effectivenessdepended on what radiation had already done in the cell cyclein terms of blocking cell division," said Dr. Duch. "Cellstreated with radiation become blocked in the G2-M phase of thecell cycle. We found that when we waited to add Navelbine untilmost of the treated cells were blocked at this stage, optimalpotentiation was observed, and that Navelbine was not effectivewhen administered prior to this time."

Radiation produced a maximum 60% to 70% block in the G2-M phaseof the cell cycle after 10 hours. Vinorelbine given early afterirradiation, when only 10% to 30% of the cells were in G2-M, producedcell survival ratios similar to the controls treated with radiationalone.