Modification of the response of a quiescent cell population within a murine solid tumour to boron neutron capture irradiation: studies with nicotinamide and hyperthermia

Abstract

C3H/He mice bearing SCC VII tumours received 5-bromo-2'-deoxyuridine (BrdU) continuously for 5 days via implanted mini-osmotic pumps, to label all proliferating (P) cells. 20 min after intraperitoneal injection of sodium borocaptate-10B (BSH), or 3 h after oral administration of dl-p-boronophenylalanine-10B (BPA), the tumours were irradiated with thermal neutrons. To modify the uptake dose of 10B, nicotinamide (NA) was intraperitoneally injected 60 min before the administration of 10B-compounds and/or the tumours were heated to 41.5 degrees C for 20 min immediately before irradiation. After irradiation, the tumours were excised, minced and trypsinized. The tumour cell suspensions were then incubated with cytochalasin-B (a cytokinesis-blocker). The micronucleus (MN) frequency in cells not BrdU-labelled (quiescent (Q) cells) was determined using immunofluorescence staining for BrdU. With or without the administration of 10B-compounds, the sensitivity of Q cells was lower than that of total (P + Q) tumour cells. With thermal neutron irradiation in the presence of either BPA or BSH, the MN frequency in each cell population was increased. A greater increase in the MN frequency of total tumour cells was observed after thermal neutron irradiation in the presence of BPA than in the presence of BSH. The distribution of 10B from BPA into tumour cells was thought to be more dependent on the uptake ability of the tumour cells than that from BSH. Sufficient quantity of 10B from these two 10B-compounds to cause a highly lethal event inside the cancer cell with thermal neutron irradiation could not be delivered to Q cells. When NA and/or heat treatment were combined with 10B-compound administration, NA increased MN frequency in the BSH treated total cells, and heat treatment elevated MN frequency in Q cells. From the viewpoint of cell kill effect, the combined treatment with nicotinamide and heat treatment was more useful than treatment with either nicotinamide or heat treatment alone, not only in the total tumour cells but also in the Q cells.