Histamine, leukotriene C4 and interleukin-2 increase antibody uptake into a human carcinoma xenograft model.
Systemically administered radiolabelled anti-tumour antibody is ineffective in treating the majority of patients with liver metastasis from colorectal carcinoma. We have assessed whether agents which increase capillary permeability can increase tumour uptake of antibody isotope conjugate. We developed a xenograft model of colorectal carcinoma using an antibody directed against carcinoembryonic antigen (CEA). Tumours were grown subcutaneously in the hind limbs of athymic rats to derive their circulation from the femoral artery. Cannulae were placed in the common iliac artery and iliolumbar vein. Antibody was delivered systemically, regionally and regionally with histamine, leukotriene C4 and interleukin-2. Regionally administered anti-CEA antibody resulted in a significantly greater (P = 0.004) tumour to normal tissue ratio (1.66, s.d. = 0.68) compared to systematically administered antibody (1.25, s.d. = 0.73). The addition of vasoactive drugs produced an approximately 3-fold increase with an increase to a mean tumour:liver ratio of 3.24 (s.d. = 1.39) for histamine (P less than 0.001 compared to systemic delivery), 3.21 (s.d. = 1.13, P less than 0.001) for leukotriene C4 and 3.80 (s.d. = 1.53, P less than 0.001) for interleukin-2. The addition of histamine significantly (P = 0.004) increased the mean tumour to liver ratio (1.73, s.d. = 0.44) of non-specific antibody uptake compared with either systemic (1.12, s.d. = 0.24) or regional delivery (1.25, s.d. = 0.54) of non-specific antibody alone. Increasing tumour capillary permeability can produce a significant clinically useful increase in tumour uptake of antibody-isotope conjugate.
Department of Surgery, Charing Cross and Westminister Medical School, London, UK.
T W
TW
Hennigan
R H
RH
Begent
T G
TG
Allen-Mersh
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007269:Injections, Intra-Arterial; D007376:Interleukin-2 / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D009368:Neoplasm Transplantation; D051381:Rats; D013189:SRS-A / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D007376:Interleukin-2; D013189:SRS-A; D006632:Histamine