AUGMENTATION IN CHEMOSENSITIVITY OF INTRATUMOR QUIESCENT CELLS BY COMBINED TREATMENT WITH NICOTINAMIDE AND MILD HYPERTHERMIA

C3H/He and Balb/c mice bearing SCC VII and EMT6/KU tumors, respectivel y, received continuous administration of 5-bromo-2'-deoxyuridine (BrdU ) for 5 days using implanted mini osmotic pumps to label all prolifera ting (P) cells. Nicotinamide was administered intraperitoneally before cisplatin injection and/or tumors were locally heated at 40 degrees C for 60 min immediately after cisplatin injection. The tumors were the n excised, minced and trypsinized. The tumor cell suspensions were inc ubated with cytochalasin-B (a cytokinesis-blocker), and the micronucle us (MN) frequency in cells without BrdU labeling (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. The NN fre quency in total (P+Q) tumor cells was determined from tumors that had not been pretreated with BrdU labeling. The sensitivity to cisplatin w as evaluated in terms of the frequency of induced micronuclei in binuc lear tumor cells (MN frequency). In both tumor systems, the MN frequen cy in Q cells was lower than that in the total cell population. Nicoti namide treatment elevated the MN frequency in total SCC VII cells. Mil d heating raised the MN frequency more markedly in Q cells than in tot al cells. The combination of nicotinamide and mild heat treatment incr eased the MN frequency more markedly than either treatment alone. In t otal SCC VII cells, nicotinamide increased Pt-195m-cisplatin uptake. M ild heating elevated Pt-195m-cisplatin uptake in total EMT6/KU cells. Cisplatin-sensitivity of Q cells was lower than that of total cells in both tumor systems. Nicotinamide sensitized tumor cells including a l arge acutely hypoxic fraction, such as those of SCC VII tumors, throug h inhibition of the fluctuations in tumor blood flow. Tumor cells incl uding a large chronically hypoxic fraction such as Q cells were though t to be sensitized by mild heating through an increase in tumor blood flow.