Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics.
Cancer Res
; 53(14): 3336-42, 1993 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-8324745
ABSTRACT
The calicheamicin family of antitumor antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Their potency suggested that the calicheamicins would be excellent candidates for targeted delivery and a hydrazide prepared from the most potent and abundant of the naturally occurring derivative, gamma 1I, was linked to oxidized sugars on CT-M-01, an internalizing anti-polyepithelial mucin antibody. The conjugates retained the immunoreactivity of the unmodified antibody and were specifically cytotoxic toward antigen positive tumor cells in vitro and in vivo. Hydrazide analogues of less potent calicheamicin derivatives were also prepared and conjugated to CT-M-01. Comparison of the therapeutic efficacy of the conjugates against the MX-1 xenograft tumor implanted s.c. in nude mice showed that conjugates of derivatives missing the rhamnose, a sugar residue that is part of the DNA binding region of the drug, were not as promising as antitumor therapies. However, conjugates of two derivatives, alpha 3I and N-acetyl-gamma 1I, in which the rhamnose residue is present but the amino sugar residue of the parent drug is either missing or modified, significantly inhibited tumor growth over a 4-fold dose range and produced long-term tumor-free survivors. Sterically hindering methyl groups adjacent to the disulfide in the linker further increased the therapeutic window of these potent conjugates.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Antibacterianos
/
Antibióticos Antineoplásicos
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
1993
Tipo del documento:
Article