PMID- 8113865
OWN - NLM
STAT- MEDLINE
DCOM- 19940330
LR  - 20041117
IS  - 0022-3085 (Print)
IS  - 0022-3085 (Linking)
VI  - 80
IP  - 3
DP  - 1994 Mar
TI  - Efficacy of direct intratumoral therapy with targeted protein toxins for solid 
      human gliomas in nude mice.
PG  - 520-6
AB  - Targeted protein toxins are a new class of reagents with the potential for great 
      tumor selectivity and cytotoxic potency. Two such compounds were studied: 1) 
      Tf-CRM107, a conjugate of human transferrin (Tf) and diphtheria toxin with a 
      point mutation (CRM107); and 2) 454A12-rRA, a conjugate of a monoclonal antibody 
      (454A12) to the human Tf receptor and recombinant ricin A chain (rRA). Both 
      compounds are potent and specific in killing human glioblastoma cell lines in 
      vitro. The authors investigated the activity of these reagents administered 
      intratumorally against solid U251 MG human gliomas in vivo. Nude mice with 
      established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were randomly 
      assigned to be treated with 100-microliters intratumoral injections of Tf-CRM107 
      (10 micrograms) or 454A12-rRA (10 micrograms), equimolar doses of CRM107 (4.3 
      micrograms), 454A12 antibody (7.5 micrograms), or rRA (1.5 micrograms), or 
      phosphate-buffered saline (PBS) every 2 days for a total of four doses. Tumor 
      volume and animal weight were assessed by a blinded observer before each 
      treatment and biweekly for 30 days after initiating therapy. With Tf-CRM107 
      administration, tumor regression of greater than 95% occurred by Day 14 (p < 
      0.01) and tumors did not recur by Day 30. Treatment with 454A12-rRA caused a 30% 
      decrease in tumor volume by Day 14 (p < 0.01). Treatment with equimolar doses of 
      the unconjugated targeted protein toxin components CRM107, 454A12, or rRA caused 
      significant U251 MG tumor growth inhibition, but the effects were less potent 
      than the antitumor effects of the conjugates. This study also characterized the 
      dose-response effect of Tf-CRM107 on tumor growth and tumor weight on Day 30. 
      Nude mice with established U251 MG flank tumors (0.5 to 1.0 cm in diameter) were 
      treated with 100-microliters intratumoral injections of 10, 1.0, or 0.1 microgram 
      of Tf-CRM107 or PBS every 2 days for a total of four doses. All three doses of 
      Tf-CRM107 significantly inhibited tumor growth by Day 14 (p < 0.01) and at Day 30 
      (p < 0.05), with a significant dose-response relationship. This study 
      demonstrated in vivo efficacy of the targeted toxins Tf-CRM107 and 454A12-rRA 
      against a human glioma. With intratumoral administration, the effect of Tf-CRM107 
      was tumor-specific and in some animals curative. Regional therapy with these 
      potent tumor-specific agents using direct intratumoral infusion should limit 
      systemic toxicity and may be efficacious against brain tumors.
FAU - Laske, D W
AU  - Laske DW
AD  - Surgical Neurology Branch, National Institute of Neurological Disorders and 
      Stroke, National Institutes of Health, Bethesda, Maryland.
FAU - Ilercil, O
AU  - Ilercil O
FAU - Akbasak, A
AU  - Akbasak A
FAU - Youle, R J
AU  - Youle RJ
FAU - Oldfield, E H
AU  - Oldfield EH
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Neurosurg
JT  - Journal of neurosurgery
JID - 0253357
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Bacterial Toxins)
RN  - 0 (CRM 107)
RN  - 0 (Diphtheria Toxin)
RN  - 0 (Immunotoxins)
RN  - 0 (Receptors, Transferrin)
RN  - 0 (Recombinant Proteins)
RN  - 9009-86-3 (Ricin)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*administration & dosage
MH  - Bacterial Toxins/*administration & dosage
MH  - *Diphtheria Toxin
MH  - Glioma/*drug therapy
MH  - Humans
MH  - Immunotoxins/*therapeutic use
MH  - Mice
MH  - Mice, Nude
MH  - Receptors, Transferrin
MH  - Recombinant Proteins/administration & dosage
MH  - Ricin/*administration & dosage
MH  - Tumor Cells, Cultured
EDAT- 1994/03/01 00:00
MHDA- 1994/03/01 00:01
CRDT- 1994/03/01 00:00
PHST- 1994/03/01 00:00 [pubmed]
PHST- 1994/03/01 00:01 [medline]
PHST- 1994/03/01 00:00 [entrez]
AID - 10.3171/jns.1994.80.3.0520 [doi]
PST - ppublish
SO  - J Neurosurg. 1994 Mar;80(3):520-6. doi: 10.3171/jns.1994.80.3.0520.