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Characterization of an antineoplastic glucuronide prodrug
T L Cheng1, W C Chou, B M Chen
1Graduate Institute of Life Sciences, National Defense Medical School, Academia Sinica, Taipei, Taiwan.
Biochemical Pharmacology
|July 28, 1999
Summary
The anticancer prodrug p-hydroxyaniline mustard glucuronide (BHAMG) is less toxic because it enters cells poorly and has low activity. Optimal tumor cell killing requires its activation outside cells using antibody-enzyme conjugates.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Tumor therapy specificity can be enhanced by activating prodrugs at targeted tumor cells.
- Antibody-enzyme conjugates enable targeted activation of prodrugs.
Purpose of the Study:
- Investigate conditions for efficient activation of p-hydroxyaniline mustard glucuronide (BHAMG) to p-hydroxyaniline mustard (pHAM).
- Determine the factors contributing to BHAMG's reduced toxicity and optimal activation site.
Main Methods:
- Compared DNA cross-linking activity of BHAMG and pHAM.
- Measured partition coefficients in an octanol-water system.
- Assessed BHAMG toxicity in BHK cells expressing cytosolic or secreted beta-glucuronidase (betaG).
Main Results:
- pHAM is 180-fold more potent than BHAMG at inducing DNA cross-links.
- BHAMG exhibits significantly lower toxicity and cellular uptake compared to pHAM.
- Extracellular betaG is essential for optimal BHAMG activation, leading to enhanced cytotoxicity.
Conclusions:
- BHAMG's low toxicity is attributed to hindered cellular uptake and reduced alkylating activity.
- Enzymatic activation of BHAMG outside tumor cells is crucial for maximizing cytotoxicity.
- Non-internalizing antibodies are preferred for targeted antibody-enzyme activation of BHAMG in human tumor therapy.