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PubMedDate not supplied

Antitumor effects of an antibody-carboxypeptidase G2 conjugate in combination with a benzoic acid mustard prodrug.

The F(ab')2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme prodrug therapy (ADEPT). The prodrug, 4-[(2-chloroethyl) (2-mesyloxyethyl)amino]-benzoyl-L-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer.

Animals↗

PubMed1993

The effects of a benzoic acid mustard derivative of distamycin A (FCE 24517) and related minor groove-binding distamycin analogues on the activity of major groove-binding alkylating agents.

The distamycin derivative FCE 24517 is a potent antitumour agent. Efforts have been made towards elucidating the mechanism of action of this compound which, to date, have highlighted a high level of DNA sequence specificity for covalent adduct formation. Compared to classical alkylating agents, FCE 24517 forms very few covalent adducts with double-stranded DNA, and thus appears to be a weak alkylating agent. Examination of the effects of this minor groove-binding agent on the major groove of DNA have been facilitated by use of the alkylating agents mustine, melphalan, dabis maleate, quinacrine mustard and uracil mustard. Pretreatment of plasmid DNA with FCE 24517 followed by reaction with any one of these mustards gave rise to a marked abolition of N-7 guanine adduct formation, as assayed by Maxam and Gilbert sequencing gels. The smallest effect was seen for quinacrine mustard, whereas total abolition of N-7 guanine alkylation was seen with uracil mustard. Using related structural analogues of FCE 24517 in the same experiments, it was not possible to reproduce this effect, with very few exceptions. Some effects were seen when using distamycin A itself in these experiments, although these were marginal compared to those seen for FCE 24517. We were able to extrapolate our findings to a whole cell system using murine L-1210 leukaemia cells. Alkaline elution experiments showed that treatment of cultured cells with FCE 24517 followed by either mustine or uracil mustard caused a marked inhibition of DNA interstrand crosslink formation, compared to treatment with mustine or uracil mustard alone. The present study has demonstrated the marked effect that FCE 24517 has upon the reactivity of double-stranded DNA, an effect possibly separate from that of its alkylating function. This study has highlighted the complex nature of the DNA interactive compound FCE 24517 which possess potent and broad spectrum antitumour activity.

Alkylating Agents↗

PubMed2001

Melanocyte-Directed enzyme prodrug therapy (MDEPT): development of second generation prodrugs for targeted treatment of malignant melanoma.

Evaluation of second generation prodrugs for MDEPT, by oximetry, has highlighted structural properties that are advantageous and disadvantageous for efficient oxidation using mushroom tyrosinase. In particular, a sterically undemanding prodrug bis-(2-chloroethyl)amino-4-hydroxyphenylaminomethanone 28 was synthesised and found to be oxidised by mushroom tyrosinase at a superior rate to tyrosine methyl ester, the carboxylic acid of which is the natural substrate for tyrosinase. The more sterically demanding phenyl mustard prodrugs 9 and 10 were oxidised by mushroom tyrosinase at a similar rate to tyrosine methyl ester. In contrast, tyramine chain elongation via heteroatom insertion was detrimental and the rate of mushroom tyrosinase oxidation of phenyl mustard prodrugs 21 and 22 decreased by 10 nanomol/min.

Agaricales↗

PubMed1970