DRUG AND RADIATION-RESISTANCE IN SPHEROIDS - CELL CONTACT AND KINETICS

Cells from multicellular spheroids are often more resistant than monol ayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the dru g to penetrate the spheroid, or the presence of hypoxic cells, these m echanisms do not adequately explain resistance to all agents. Small sp heroids (containing about 25-50 cells) exposed to ionizing radiation, hyperthermia, photodynamic therapy, or topoisomerase II inhibitors, ar e more resistant to killing than monolayers; the close three-dimension al contact in spheroids has been implicated in this resistance. Propos ed mechanisms for the 'contact effect' include gap junctional 'recipro city', cell shape mediated changes in (repair-related) gene expression , and alterations in chromatin packaging which influence DNA repair. T he consequences of the contact effect are especially important for mul tifraction exposures. Another form of resistance can be demonstrated d uring repetitive treatments; 'regrowth resistance' reflects the capaci ty of spheroid cells to proliferate more efficiently to compensate for cell killing.