Tumor‐specific Alkaline Phosphatase in Hepatoma

Suzuki, Hiroshi; Iino, Shiro; Endo, Yasuo; Torii, Masao; Oda, Tatsuya

doi:10.1111/j.1749-6632.1975.tb25427.x

Cited by 32 publications

(14 citation statements)

References 12 publications

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“…Because 125 IQ 2-P is rapidly cleared from the blood and body following i.v. injection (0.01 -0.4% ID/g remains in all normal tissues at 24 h), 3 we believe that the f30% of the injected dose that is released into circulation from within the injected tumor will be cleared with similar pharmacokinetics. The current results, which also indicate that the radioactive content of the blood and contralateral muscle is very low (0.09 F 0.03%/g and <0.005 F 0.007%/g, respectively), show that very high tumor-to-blood (f800) and tumor-to-muscle (f13,500) ratios can be achieved on the in vivo hydrolysis of this quinazolinone derivative.…”

Section: Chemical Studiesmentioning

confidence: 84%

“…injection show minimal retention in all normal tissues (0.01 -0.4% ID/g at 24 h after injection). 3 These findings indicate that the compound has minimal affinity to normal cells and is not significantly hydrolyzed by them.…”

Section: Introductionmentioning

confidence: 89%

“…The synthetic details of compounds 5 to 8 will appear elsewhere. 3 Radiolabeled ( 125 I) Ammonium 2-(2 ¶-Phosphoryloxyphenyl)-6-Iodo-4-(3H)-Quinazolinone ( 125 IQ 2-P ) (8). Phosphate buffer (10 AL, 0.01 mol/L, pH 7.4) and ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-tributylstannyl-4-(3H)-quinazolinone (6; 1 AL of 5 Ag/AL DMSO solution) were placed in a reaction vial coated with 1,3,4,6-tetrachloro-3a,6a-diphenylglycouril (Iodogen, 10 Ag).…”

Section: Methodsmentioning

confidence: 99%

“…Similar findings (minimal fluorescence or its absence) are also obtained following a 24-h incubation of normal mouse tissues (kidneys, liver, and spleen) with IQ 2-P . 3 We also examined the capacity of NE tumor cells grown in vivo as solid tumors to hydrolyze IQ 2-P in vitro. Mouse Enzyme-Mediated Cancer Diagnosis and Therapy NE teratocarcinoma cells were injected i.m.…”

Section: Chemical Studiesmentioning

confidence: 99%

“…Further studies have shown that IQ 2-P(I) (10) is not hydrolyzed by alkaline phosphatase and the injection of 125 IQ 2-P(I) (7) into normal mice leads to the localization of approximately 10% to 15% ID/g in liver and kidneys. 3 On the other hand, IQ 2-P (4) and 125 IQ 2-P (8) are readily hydrolyzed by alkaline phosphatase and their pharmacokinetics in normal mice following i.v. injection show minimal retention in all normal tissues (0.01 -0.4% ID/g at 24 h after injection).…”

Section: Introductionmentioning

confidence: 99%

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In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

Chen

Wang

Kirichian

et al. 2006

Molecular Cancer Therapeutics

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As part of the development of enzyme-mediated cancer imaging and therapy, a novel technology to entrap waterinsoluble radioactive molecules within solid tumors, we show that a water-soluble, radioactive quinazolinone prodrug, ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-[ 125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-P ), is hydrolyzed by alkaline phosphatase to a water-insoluble, radiolabeled drug, 2-(2 ¶-hydroxyphenyl)-6-[ 125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-OH ). Biodistribution data suggest the existence of two isoforms of the prodrug (IQ 2-P(I) and IQ 2-P ), and this has been confirmed by their synthesis and characterization. Structural differences of the two isoforms have been examined using in silico molecular modeling techniques and docking methods to describe the interaction/binding between the isoforms and human placental alkaline phosphatase (PLAP), a tumor cell, membrane-associated, hydrolytic enzyme whose structure is known by X-ray crystallographic determination. Docking data show that IQ 2-P , but not IQ 2-P(I) , fits the active binding site of PLAP favorably and interacts with the catalytic amino acid Ser 92 , which plays an important role in the hydrolytic process. The binding free energies (#G binding ) of the isoforms to PLAP predict that IQ 2-P will be the better substrate for PLAP. The in vitro incubation of the isoforms with PLAP leads to the rapid hydrolysis of IQ 2-P only and confirms the in silico expectations. Fluorescence microscopy shows that in vitro incubation of IQ 2-P with mouse and human tumor cells causes the extracellular, alkaline phosphatasemediated hydrolysis of the molecule and precipitation of fluorescent crystals of IQ 2-OH . No hydrolysis is seen in the presence of normal mouse and human cells. Furthermore, the intratumoral injection of 125 IQ 2-P into alkaline phosphatase -expressing solid human tumors grown s.c. in nude rats results in efficient hydrolysis of the compound and retention of f70% of the injected radioactivity, whereas similar injection into normal tissues (e.g., muscle) does not produce any measurable hydrolysis (f1%) or retention of radioactivity at the injected site. These studies support the enzyme-mediated cancer imaging and therapy technology and show the potential of such quinazolinone derivatives in the in vivo radiodetection ( 123 I/ 124 I) and therapy ( 131 I) of solid tumors.

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Section: Chemical Studiesmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Chemical Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

Chen

Wang

Kirichian

et al. 2006

Molecular Cancer Therapeutics

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Gonadotropin and alkaline phosphatase producing occult gastric carcinoma with widespread metastasis of generalized bone

Uchida

Shikata

Shimizu

et al. 1981

Cancer

Self Cite

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A case is reported of a small primary occult gastric adenocarcinoma occurring in a 57-year-old man revealing widespread metastasis to generalized bone, and associated with high serum level of circulating human chorionic gonadotropin (hCG), carcinoembryonic antigen (CEA), and alkaline phosphatase (ALPase). The primary site of metastatic bone tumor was not clear until autopsy. Microscopic examination of the gastric primary revealed moderately differentiated tubular adenocarcinoma admixed with numerous signet-ring carcinoma cells without conspicuous trophoblastic differentiation. The elaboration of hCG and intestinal and placental isoenzyme of ALPase by carcinoma cells themselves was confirmed by the indirect immunoperoxidase method. The present case may be interesting because of unusual metastasis and simultaneous production of hCG, CEA, and intestinal and placental ALPase isoenzymes. Cancer 48:140-150, 1981.

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The prevalence of variant alkaline phosphatase in hepatocellular carcinoma in Southern African blacks

Bukofzer

Kew

Rowe

1988

Cancer

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The prevalence of variant alkaline phosphatase in the serum of 335 southern African blacks with hepatocellular carcinoma was determined using polyacrylamide gel electrophoresis. The isoenzyme was detected in 2% (seven of 335) of the patients: it could not be found in the serum of 300 matched, healthy individuals or in 56 patients with various benign hepatic diseases. Variant alkaline phosphatase is thus of little use as a diagnostic marker of hepatocellular carcinoma in southern African blacks. The reported prevalence of this isoenzyme in hepatocellular carcinoma ranges between 3% and 31%. Higher frequencies usually are recorded in populations with a low incidence of the tumor, and the lowest frequencies have been found in Chinese patients. Our finding of variant alkaline phosphatase in only 2% of another high incidence population fits this trend. Patients with tumors that secreted the variant isoenzyme had a significantly higher serum total alkaline phosphatase activity than those with tumors lacking this property.

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Tumor‐specific Alkaline Phosphatase in Hepatoma

Cited by 32 publications

References 12 publications

In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

Gonadotropin and alkaline phosphatase producing occult gastric carcinoma with widespread metastasis of generalized bone

The prevalence of variant alkaline phosphatase in hepatocellular carcinoma in Southern African blacks

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