In vitro and in vivo activities of monoclonal antibody-alkaline phosphatase conjugates in combination with phenol mustard phosphate.
The prodrug p-[N,N-bis(2-chloroethyl)amino]phenyl phosphate (phenol mustard phosphate, POMP) was prepared from p-[N,N-bis(2-chloroethyl)amino]phenol (phenol mustard, POM) by phosphorylation with phosphoryl chloride, followed by aqueous hydrolysis. It was found that POMP was much less cytotoxic than POM when tested against H2981 human lung and H3396 human breast carcinoma cells in vitro. Pretreatment of the H2981 cells with L6-alkaline phosphatase (L6-AP), a monoclonal antibody conjugate that could bind to cell surface antigens, greatly enhanced the cytotoxic effects of POMP in an immunologically specific manner. Owing to its reduced toxicity in nude mice, larger amounts of POMP compared to POM could be administered. Neither agent exhibited significant in vivo antitumor activity when tested against subcutaneous H2981 tumors in nude mice. However, antitumor activity was observed in animals receiving L6-AP 48 h prior to POMP administration. This level of activity was greater than with the drugs alone, or a combination of 1F5-AP (nonbinding control) with POMP.
Wallace
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PM
Oncogen Division, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Senter
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PD
D000469:Alkaline Phosphatase / Q000737:chemistry*; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000922:Immunotoxins; D011355:Prodrugs; C000929:hydroxyaniline mustard; C016373:hydroxyaniline mustard phosphate; D000816:Aniline Mustard; D000469:Alkaline Phosphatase