Interleukin-12 has no effect on vascular density, perfusion, hypoxia and proliferation of an implanted human squamous cell carcinoma xenograft tumour despite up-regulation of ICAM-1.
BACKGROUND
Interleukin-12 is an anti-angiogenic and antitumor agent in many transplanted murine tumour models. In a previous clinical study in head and neck squamous cell carcinoma patients treated with rhIL-12 the tumour turned pale, after an initial reddening. The aim of this study was to investigate the effects of rmIL-12 on the vasculature, blood perfusion, hypoxia and proliferation of tumour cells in an implanted human head and neck squamous cell carcinoma xenograft tumour, with a relatively large diameter, in Balb/c nu/nu mice over time.


METHODS
Established human squamous cell carcinoma xenograft tumours were intratumorally injected for 3 days with either 200 ng rmIL-12 or PBA. Mice were sacrificed at 4 different time points (between 8 hours and 8 days after the last injection), after administration of Pimonidazole, BrdUrd and Hoechst 33342. The tumour sections were quantitatively analysed with a semi-automatic method based on a computerised digital image analysis system, after immunohistochemical staining.


RESULTS
Despite a faster and higher up-regulation of anti-mouse ICAM-1 in the IL-12-treated tumours, no significant differences in vascular density, perfusion fraction, hypoxic fraction and BrdUrd labelling index were detected between IL-12-treated tumour and control tumours.


CONCLUSIONS
We suggest that the main reason why the observation made in humans could not be confirmed in this mice study is the combination of a lack of an intact immune system in the Balb/c nu/nu mice and a relatively large tumour with probably a lot of mature vessels.
van Herpen
Carla M L
CM
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, The Netherlands. C.vanherpen@onco.umcn.nl
Bussink
Johan
J
van der Kogel
Albert J
AJ
Peeters
Wenny J M
WJ
van der Voort
Robbert
R
van Schijndel
Anita
A
de Wilde
Peter C M
PC
Adema
Gosse J
GJ
de Mulder
Pieter H M
PH
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D018664:Interleukin-12