Relationship of the CD22 immunotoxin dose and the tumour establishment in a SCID mice model.
Immunotoxins (ITs) may be very potent to erradicate tumour growth in vivo. We investigated the influence of the IT-dose, in relation to the establishment of the tumour, on the anti-tumour activity of CD22-recombinant (rec) ricin A for a disseminated tumour (Ramos) in SCID mice. Furthermore, the enhancement of the IT cytotoxicity in vivo by chloroquine was assessed. CD22-rec ricin A appeared to be highly effective. Paralysis of the hind legs was significantly delayed by a very low IT-dose of 2 microg administered intravenously (i.v.) 7 days after i.v. inoculation of the tumour cells. Even a dose of 30 microg administered 21 days after inoculation of the target cells significantly delayed the onset of paralysis up to 8 days compared with the median paralysis time (MPT) of the control group. The efficacy of treatment was obviously influenced by the establishment of the tumour, the tumour load and localisation. The anti-tumour activity of 10 and 30 microg IT diminished when the IT was administered after increasing the time lag following inoculation of tumour cells. Delaying IT administration resulted in growth of solid tumours. This implies that cells migrate to sanctuaries protected from the IT indicating that the anti-tumour activity was influenced by the accessibility of the IT to the target cells. The in vivo anti-tumour activity of CD22-rec ricin A could not be enhanced by simultaneously administered chloroquine, despite the continuous infusion with an intraperitoneally (i.p.) implanted mini-osmotic pump. Ex vivo experiments revealed that the maximally tolerated serum concentration (3.9 microM) was too low to be effective. In conclusion, CD22-rec ricin A is highly effective for in vivo treatment of B-cell malignancies, in particular if treatment is started when the tumour load is low and before migration takes place to poorly accessible sanctuaries.
Van Horssen
P J
PJ
Department of Haematology and Central Haematology Laboratory, University Medical Centre St. Radboud, Nijmegen, The Netherlands.
Preijers
F W
FW
Van Oosterhout
Y V
YV
Eling
W M
WM
De Witte
T
T
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000473:pathology; D015815:Cell Adhesion Molecules; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000627:therapeutic use; D037102:Lectins; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012276:Ricin / Q000494:pharmacology; D051918:Sialic Acid Binding Ig-like Lectin 2; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D000922:Immunotoxins; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; D002738:Chloroquine; D012276:Ricin