Influence of recombinant tumour necrosis factor alpha on blood flow and antibody localisation in human tumour xenografts in nude mice.
Mice with s.c. grafts of gastric carcinoma MKN45 or osteosarcoma 788T were injected i.v. with recombinant tumour necrosis factor alpha (rTNF alpha) and tumour blood flow rates were determined 4 h later as a fraction of the cardiac output g tissue-1. With MKN45, the tumour blood flow rate was significantly reduced from a mean of 1.86% cardiac output g-1 to 0.84% and 0.65% with 50 and 200 micrograms kg-1 rTNF alpha respectively. With 788T, the tumour blood flow rate was reduced at 50 micrograms kg-1 rTNF alpha from 1.13% cardiac output g-1 to 0.56%. There were essentially no changes in blood flow rates in other organs. The effect of rTNF alpha on localisation of monoclonal antibodies into these xenografts were examined. When a single dose of rTNF alpha (50 micrograms kg-1) was given at the same time as labelled NCRC-2 antibody there was a significant reduction in localisation into 788T osteosarcoma xenografts. In other tests, mice were injected daily for 3 days with 50 micrograms kg-1 rTNF alpha. They were injected i.v. with monoclonal antibody 4 h after the first injection and dissected on the 4th day. With 788T there was a small but not statistically significant reduction in the absolute amount of NCRC-2 antibody localising in tumour, although this reduction was greater when results were expressed as tumour-to-blood ratios. With MKN45 xenografts, treatment with rTNF alpha had little effect on tumour localisation of an anti-(carcinoembryonic antigen) monoclonal antibody (NCRC-24). These studies show that TNF can be administered so as to reduce tumour blood flow and with little effect on tumour localisation of antibody, suggesting that combination therapy with TNF and antibodies or their immunoconjugates is feasible. Other studies have suggested that TNF can increase antibody localisation into tumours, but this was not seen here, and in some cases administration could reduce tumour localisation. It appears that this method of enhancing antibody localisation may be critically dependent on scheduling, and therefore it may not be extensively applicable.
Pimm
M V
MV
Cancer Research Campaign Laboratories, University of Nottingham, UK.
Gribben
S J
SJ
Morris
T M
TM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001775:Blood Circulation / Q000187:drug effects*; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis; D002302:Cardiac Output / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D007279:Injections, Subcutaneous; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000098:blood supply* / Q000378:metabolism / Q000628:therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha