Preparation of Succinyl Neocarzinostatin

Maeda, Hiroshi

doi:10.1128/aac.5.3.354

Cited by 8 publications

(2 citation statements)

References 7 publications

(3 reference statements)

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“…There is evidence that NCSconjugates are stabilized as a result of the substitution of one or both of the amino groups present in the molecule. This is probably not due to prevention of the apoprotein from proteolysis as suggested by Maeda,12) but simply the consequence of a hindered dissociation of NCS-chromophorefrom its protecting apoprotein. The chromophore is converted to an inactive species after leaving the apoprotein,22) therefore only chromophore bound to and protected by apoprotein will reach its target in active form.…”

Section: Resultsmentioning

confidence: 99%

Increased serum stability and prolonged biological half-life of neocarzinostatin covalently bound to monoclonal antibodies.

et al. 1991

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The pharmacokinetics of neocarzinostatin (NCS) have been compared to NCSconjugates with monoclonal antibodies using Balb/c and tumor bearing nude mice. Data on blood and whole body clearance revealed that the high MWconjugate persists in the body far longer and at a higher level than the free drug. Excretion of the free drug occurs with an extremely rapid renal clearance and localization of the remaining drug in the kidney, whereas the NCSimmunoconjugate remained in circulation far longer allowing time for tumor localization to occur without renal accumulation of drug.In addition, NCSconjugated to monoclonal antibody was found to retain its activity in human serum better than free drug, in agreement with data obtained for other NCS-derivatives. Half-time ofinactivation was greatly extended whenmeasured under relevant conditions in a DNAstrand-break assay.The results indicate that two of the most important requirements for the successful targeting of NCSin vivo, decreased clearance rate and increased serum stability are achieved by conjugation to antibody. Both results increase the probability of NCSaccumulating in tissue while still in its active form.Coupling ofNCSto monoclonalantibody decreases clearance and inactivation rate and increases localization of the active drug in tumor tissue.The antitumor antibiotic neocarzinostatin (NCS) has been used in clinical trials for the chemotherapy of human cancers in recent years.1>2) It is evident, however, from both in vitro and in vivo experiments, that both pharmacokinetics as well as serum stability of NCSare disadvantageous. The drug exhibits an extremely rapid renal clearance and becomes inactivated in serum with a half-life in the order of minutes.2~4)The drug consists of an apoprotein and a non covalently associated chromophorethat is very sensitive to light and heat.5) The primary structure of the apoprotein has been elucidated and revised,6) and the binding site involved in the association of the non-protein chromophore as well as the regions for hydrophobic interactions have been described.7) It was noted that the only two amino-groups present in the protein (one a-amino-group at Ala 1, one e-amino-group at Lys 20) are not involved in the cytotoxic action and therefore modification at one or both of these functionalities results in no loss of biological activity.8) Conjugates of NCSand a variety of markers such as fluorescein,9) rhodamine or biotin (Gottschalk, U.; A. Maibucher and K. Trutschler-Ebert; unpublished data), peroxidase,10) SMA,1 1} succinyl,12) transferrin13) and monoclonal antibodies14) have been prepared via the NH2-groups in studies on NCSand its possible role in tumor therapy. In the present study the pharmacokinetics and serum stability of conjugates of NCSand the monoclonal antibody 791T/36 have been examined. This has

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Section: Resultsmentioning

confidence: 99%

Increased serum stability and prolonged biological half-life of neocarzinostatin covalently bound to monoclonal antibodies.

et al. 1991

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“…NCS was obtained from Kayaku Antibiotic Research Laboratories, Tokyo, and repurified as described (12). The 14C derivative was prepared by chemical modification using [1,4-14C]succinic anhydride (9,10). Its specific radioactivity was 5.0 x 106 cpm/mg of protein.…”

Section: Methodsmentioning

confidence: 99%

Mechanism of Accumulation of the Antitumor Protein Antibiotic Neocarzinostatin in Bladder Tissue: Intravenous Administration, Urinary Excretion, and Absorption into Bladder Tissue

Maeda

Sakamoto

Ogata

1977

Antimicrob Agents Chemother

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Some aspects ofthe absorption, distribution, and excretion of neocarzinostatin (NCS), a proteinous antitumor antibiotic, were studied in rabbits. NCS was given intravenously (i.v.) via the auricular vein, or [14I]NCS was instilled directly into the cavity of the bladder by tubing. In both groups, ureterostomy was performed, so that the drug excreted in the urine did not pass through the bladder. The results showed extremely rapid renal clearance; namely, twothirds of the total recovered was excreted in the first 5 min. It was also shown that drug infused into the bladder cavity could be recovered in urine from the ureterostomized ureter. Also, the level of biological activity of NCS in bladder tissues after i.v. administration is significantly lower when ureterostomy is performed. Thus, evidence is presented for the absorption of NCS into bladder tissue from the lumen of the bladder. The high levels of NCS in bladder tissue are due to this effect as well as to accumulation via the iliac artery. These data should encourage further trials of NCS in bladder cancer. A study of urine containing NCS derived from i.v. administration showed an increase in antibacterial activity upon incubation, followed by a decrease. These effects are probably due to proteolysis, as shown by the appearance of a low-molecular-weight fragment and by the absence of such an increase in the presence of inhibitors of proteolysis.

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Pharmacological Uniqueness and Clinical Effects of Neocarzinostatin

Maeda

1997

Neocarzinostatin

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Preparation of Succinyl Neocarzinostatin

Cited by 8 publications

References 7 publications

Increased serum stability and prolonged biological half-life of neocarzinostatin covalently bound to monoclonal antibodies.

Increased serum stability and prolonged biological half-life of neocarzinostatin covalently bound to monoclonal antibodies.

Mechanism of Accumulation of the Antitumor Protein Antibiotic Neocarzinostatin in Bladder Tissue: Intravenous Administration, Urinary Excretion, and Absorption into Bladder Tissue

Pharmacological Uniqueness and Clinical Effects of Neocarzinostatin

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