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Efficacy of direct intratumoral therapy with
targeted protein toxins for solid human gliomas in nude mice
Laske DW, Ilercil O, Akbasak A, Youle RJ, Oldfield EH
Surgical Neurology Branch, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
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.
PMID: 8113865 [PubMed - indexed for MEDLINE]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8113865
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