The sequential changes in DNA synthesis, glucose utilization, protein synthesis, and peripheral benzodiazepine receptor density in C6 brain tumors after chemotherapy to predict the response of tumors to chemotherapy.
BACKGROUND
Monitoring therapy in patients with brain tumors is very difficult and unreliable. It has been shown that there is no good correlation between tumor sensitivity measured in vitro and in situ tumor response to therapies.


METHODS
Sequential changes in tumor size, number of DNA synthesizing cells (labelling index [LI]), glucose utilization (LCGU), protein synthesis (LCPS), and peripheral benzodiazepine receptor (PBR) density were examined after chemotherapy for seven days. This was done using antibromodeoxyuridine immunohistochemical stain and multiple tracer quantitative autoradiography in a C6 rat brain with an implanted glioma. On Day 10 after inoculation, the rats were divided into 5 experimental groups: (1) a nontreatment group (control Group 1); (2) a group received 5% dextrose intraarterial (IA) administration (control Group 2); (3) a group received 1,3-bis-(2-chloroethyl) nitrosourea (BCNU) intravenous (i.v.) administration (Group 3) (5% dextrose was solvent); (4) a group received BCNU IA administration (Group 4) (5% dextrose was solvent); and (5) a group received sarcosinamide chloroethyl nitrosourea (SarCNU) IA administration (Group 5) (solvent as for the BCNU group).


RESULTS
Three treatments showed a significant decrease (P < 0.003) in tumor growth. The most effective treatment was BCNU IA and SarCNU IA was moderately effective. BCNU i.v. showed no effect on tumor growth when compared with the two control groups. The change in the peak LI correlated well with the peak LCGU. These parameters decreased markedly and significantly in both Group 4 and Group 5 from Day 1 after treatment. The rates of the decrease in these biologic factors also correlated well with a decrease in the tumor growth. The LCPS did not correlate with a decrease in the LI or LCGU. The dissociation constant (Kd) and densities of the receptors PBR (B max) did not change significantly in any of the treatment groups during the observation period.


CONCLUSIONS
From the results presented, we concluded that changes in the LI and LCGU represent the most reliable parameters with which to predict the response or sensitivity of this glial tumor to the treatments applied. These data suggest that if changes in peak LCGU were measured in tumors using positron emission tomography, they might be instrumental in providing in vivo information about the sensitivity of a tumor to a given treatment without the need for repeated tumor biopsy.
Takeda
N
N
Cone Laboratory for Neurosurgical Research, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Diksic
M
M
Yamamoto
Y L
YL
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002330:Carmustine / Q000627:therapeutic use; D004247:DNA / Q000096:biosynthesis*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D008991:Monitoring, Physiologic; D014176:Protein Biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000032:analysis*
D018906:Antineoplastic Agents, Alkylating; D011963:Receptors, GABA-A; D004247:DNA; D001973:Bromodeoxyuridine; D005947:Glucose; D002330:Carmustine