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Blocking effect of human serum but not of cerebrospinal fluid on ricin A chain immunotoxin potentiation by monensin or carrier protein-monensin conjugates.

Abstract：

:The potentiation of monoclonal antibody/ligand toxin (immunotoxin) cytotoxicity by the ionophore monensin (Mo) or by human serum albumin-monensin (HSA-Mo) conjugates was investigated. Since disulfide cross-linked HSA-Mo (HSA-SPDP-Mo) is rapidly inactivated by human serum (M. Colombatti et al., Cancer Res., 50: 1385-1391, 1990), we synthesized thioether cross-linked HSA-Mo conjugates (HSA-SIA-Mo). HSA-SIA-Mo is resistant to treatment with reducing agents (e.g., glutathione, dithiothreitol) and shows potentiating activity identical to that of Mo or of HSA-SPDP-Mo, enhancing immunotoxin (IT) cytotoxicity 45-35,000-fold. Human leukemic and tumor cell lines are highly sensitive to treatment with IT in combination with Mo, HSA-SPDP-Mo, or HSA-SIA-Mo (concentration required to inhibit protein synthesis by 50%, 10(-10)-2.5 x 10(-13) M). IT potentiation by both types of HSA-Mo conjugates, however, is inhibited by whole human serum. In contrast, human cerebrospinal fluid has no effect on the potentiation of IT by Mo or HSA-Mo conjugates. The serum blocking factors reside mostly in a Mr 40,000-90,000 protein fraction. Serum components of low molecular weight (less than 10,000) show no detectable effect upon the stability of HSA-Mo conjugates. The toxicity of HSA-SIA-Mo in vivo was investigated by intrathecal injections in rats. Concentrations of up to 60 micrograms/kg can be injected into the brain with only transient neurological sequelae. We therefore conclude that if the systemic delivery of HSA-Mo conjugates for the potentiation of ricin A chain-IT presents some limitations due to the blocking effect of serum, the application of HSA-Mo conjugates in combination with ricin A chain-IT for regional tumor therapy in the brain appears more promising.

journal_name

Cancer Res

journal_title

Cancer research

authors

Candiani C,Franceschi A,Chignola R,Pasti M,Anselmi C,Benoni G,Tridente G,Colombatti M

subject

Has Abstract

pub_date

1992-02-01 00:00:00

pages

623-30

issue

eissn

0008-5472

issn

1538-7445

journal_volume

pub_type

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Blocking effect of human serum but not of cerebrospinal fluid on ricin A chain immunotoxin potentiation by monensin or carrier protein-monensin conjugates.