Cancer alkaline phosphatase

Acid- and alkaline phosphatases act on a variety of mono- and multiple phosphate carrying low molecular mass molecules. In addition, they hydrolyze many, but not all, phosphoproteins. They are in use for decades to easily screen for diseases, however, somewhat unspe-cifially. For instance, acid phosphatase is used as biomarker for prostate cancer, and alkaline phosphatase to monitor bone (de-) mineralization and liver tumors. 

Kim, I.Y., Han, S.Y., and Kang, T.S. et al. (2005). Pyrethroid insecticides, fenvalerate and permethrin, inhibit progesterone-induced alkaline phosphatase activity in T47D human breast cancer cells. Journal of Toxicology and Environmental Health—Part A—Current Issues 68, 2175-2186. 

The commonest causes of obstructive (posthepatic) jaundice are cancer of the head of the pancreas and a gallstone lodged in the common bile duct. The presence of bilirubin in the urine is sometimes referred to as choluria—therefore, hepatitis and obstruction of the common bile duct cause choluric Jaundice, whereas the Jaundice of hemolytic anemia is referred to as acholuric. The laboratory results in patients with hepatitis are variable, depending on the extent of damage to parenchymal cells and the extent of micro-obstruction to bile ductules. Serum levels of ALT and AST are usually markedly elevated in hepatitis, whereas serum levels of alkaline phosphatase are elevated in obstructive liver disease. 

Amifostine is hydrolyzed rapidly to 2-[(3-aminopropyl)amino]ethane-thiol (9.64) at the acidic pH of the stomach, and by alkaline phosphatases in various tissues. After intravenous administration to cancer patients, the plasma half-lives were found to be in the order of minutes. This is highly relevant, since most or all pharmacological effects of amifostine can be ascribed to its thiol metabolite. 

In 70 postmenopausal women with completely resected breast cancers who were disease-free after taking tamoxifen for 2—3 years, a switch to exemestane resulted in increases in serum bone alkaline phosphatase and the carboxy-terminal telopeptide of type I collagen and a fall in parathormone bone mineral density worsened (28). 

The consequence of the partial agonistic activity of tamoxifen is that complete blockade of the action of estrogens cannot be achieved with tamoxifen (Wakeling, 1993) or the other compounds demonstrated to exert stimulatory effects, reversible with EM-652 on the proliferation of human breast cancer cells and alkaline phosphatase in human endometrial carcinoma cells. It is thus reasonable to expect that the availability of a pure antiestrogen, in addition to avoiding the risk of inducing endometrial carcinoma, should provide significant benefits over tamoxifen in the treatment of breast cancer. 

Using the Bodansky (B18, 52) procedure with 8-glycerophosphate as substrate, Woodard (W8) was unable to obtain such elevations. She determined the serum acid phosphatase activities in 83 females and 342 males, or a total of 425 patients with miscellaneous diseases. Of these, 61 had various types of infectious or metabolic disorders, including 11 cases of inflammatory disease of bone and 12 cases of hepatic cirrhosis. The remainder had some type of neoplastic disease and about one-third had metastases to bone from cancer of various primary sites. There were 15 cases of osteogenic sarcoma and 32 cases of osteitis deformans. All these cases, whether their serum alkaline phosphatase activities were elevated or not, had serum acid phosphatase values that were essentially within the normal range, 0.06-0.89 Bodansky unit for females and 0.11-0.88 unit for males. In contrast to the Gutman method (GIO, G14), there-... 

A transient, moderate, and reversible rise in leukocyte alkaline phosphatase, lactate dehydrogenase (LDH) and serum uric acid concentrations is usually observed in cancer patients receiving supportive treatment with GM-CSF or G-CSF. Serum LDH increased from 37 to 85% and there was a linear relation between increased leukocyte production and the rise in serum LDH (32). Increases in serum LDH activity should therefore not be interpreted as indicative of disease progression, unless LDH activity remains high after growth factor withdrawal. 

Given the above preclinical observations, patients in a clinical study were monitored closely during treatment (including measurement of testosterone, luteinizing hormone, follicle-stimulating hormone levels, alkaline phosphatase, and serum vitamin A concentrations). This phase I clinical study of TAG-101 was conducted to determine the safety, toxicity, and pharmacokinetics of this agent in patients with advanced cancer. Currently, the drug is in a phase I/II clinical trial for advanced hepatocellular carcinoma. 

Fishman WH, Inglis NR, Stolbach LL, Krant MJ. A serum alkaline phosphatase isoen2yme of human neoplastic cell origin. Cancer Res 1968 28 150-54. 

Stigbrand T, Wahren B. Alkaline phosphatase as tumor markers. In Sell S, ed. Serological cancer markers. Totowa NJ Humana Press, 1992 135-49. 

Measurement of serum y-GT activity has clinical significance. The enzyme is present in all tissues, but the highest level is in the kidney however, the serum enzyme originates primarily from the hepatobiliary system. Elevated levels of serum y-GT are found in the following disorders intra- and posthepatic biliary obstruction (elevated serum y-GT indicates cholestasis, as do leucine aminopeptidase, 5 -nucleotidase, and alkaline phosphatase) primary or disseminated neoplasms some pancreatic cancers, especially when associated with hepatobiliary obstruction alcohol-induced liver disease (serum y-GT may be exquisitely sensitive to alcohol-induced liver injury) and some prostatic carcinomas (serum from normal males has 50% higher activity than that of females). Increased activity is also found in patients receiving phenobarbital or phenytoin, possibly due to induction of y-GT in liver cells by these drugs. 

Calcitonin is used in the treatment of Paget s disease (osteitis deformans), a chronic disorder characterized by increased bone remodeling, normocalcemia and normophosphatemia, frequent episodes of hypercalciuria leading to stone formation, and elevation of serum alkaline phosphatase and urinary hydroxyproline levels. The disease does not appear to be primarily a derangement of calcium metabolism. Calcitonin reduces the levels of serum alkaline phosphatase and urinary hydroxyproline, and may relieve other symptoms of the disease as well. Diphosphonates, especially etidronate disodium, also reduce bone resorption in this disease. Various cancers are accompanied by hypercalcemia and may respond to treatment with calcitonin. 

In 1961 Nisselbaum et al. (N22) concluded that the major portion of serum alkaline phosphatase was osteogenic in origin because approximately 66% of the alkaline phosphatase in the sera of three normal patients was precipitated by antihuman bone phosphatase sera. This percentage was appreciably higher in five cancer patients (two with liver metastases, two with bone metastases, and one with metastases to both liver and bone). However, the antibone pho hatase serum precipitated liver and kidney alkaline phosphatase as effectively as it did bone. The authors were not willing for other reasons to attribute to kidney and liver a role as tissue sources of serum alkaline phosphatase, but favored bone as the major source. Pelichova et al. have extended the work on intestine (P3). 

Fig. 36. Case A. Hyperphosphatasemia during androgen therapy in cancer of the endometrium. D-total = total alkaline phosphatase activity, non-LPSAP = activity in the presence of L-phenylalanine open circles, and n — l = LPSAP, closed circles. The same symbols apply to Figures 37, 38, and 39.

Case A (Fig. 36). This female patient (blood type B) with cancer of the endometrium metastatic to liver and lung showed no change in alkaline phosphatase on the first 60 days of Delalutin (progesterone) therapy, and then showed a rise for the next 80 days. The elevated values over this period showed a reasonably close proportionate rise in the LPSAP and non-LPSAP. This circumstance applies also to the heat-sensitive and -insensitive fractions. The percent heat inactivation remains constant for both LPSAP and non-LPSAP moieties at 62 and 50%... 

Case B (Fig. 37). This female patient (blood type A) with cancer of the breast metastatic to bone showed a rise in alkaline phosphatase while on androgen (Halotestin) therapy. There was a proportionate increase in both LPSAP and non-LPSAP moieties, which could be attributed to the alteration in the heat-sensitive portions the heat-insensitive fractions showed no appreciable alteration. With the increase, the per-... 

Case C (Fig. 38). A female patient with cancer of the breast metastatic to bone exhibited a drop in serum alkaline phosphatase while on androgen therapy. This diminution can be attributed to the loss of... 

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