Timing of indomethacin in the control of prostaglandins, osteoclasts and bone destruction produced by VX2 carcinoma in rabbits

Galasko, C. S. B.; Rawlins, Richard G.; Bennett, A. B.

doi:10.1038/bjc.1979.189

Cited by 22 publications

(13 citation statements)

References 9 publications

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“…Carcinogens or transplantable tumors have been used in experimental bone invasion models of oral carcinoma (7,19,(23)(24)(25). Carcinogens such as 9,10-dimethyl 1,2-benzanthracene (DMBA) and 4-nitroquinoline N-oxide (4-NQO) are often used to experimentally induce carcinoma (7,25).…”

Section: Discussionmentioning

confidence: 99%

“…However, they all have shortcomings, such as complex preparation procedures, and such carcinogens require a long duration for establishment of an animal model, making it difficult to obtain a standardized model. Many studies on tumor invasion using a transplantable tumor, such as mouse NR-S1 tumor (19), VX2 tumor (23), and VX7 tumor (24), have been reported. To make an experimental model for gingival carcinoma invading bone tissue, a piece of tumor was transplanted directly into the extraction socket in the present study.…”

Section: Discussionmentioning

confidence: 99%

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Experimental Transplantation of Carcinoma to Tooth Extraction Sockets: A bone invasion model

et al. 2003

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Previous study has indicated that as the tumor invades the bone, a layer of collagen is formed between the tumor and the surface of the bone, and that collagen fibers are also presented in resorption pits and around tumor cells which have invaded the bone (7). The interaction of tumor cells with the ECM (extracellular matrix) plays a central role in the multistep process of tumor invasion (15). Recent studies have shown that the tumor cells synthesize collagen, which is the main component of the ECM (16,17).The purpose of this study was to use a mouse model of oral carcinoma in order to observe the process of bone invasion, and to determine whether collagen synthesis is the nutritional mediator for the tumor invading the bone. Material and Methods Animals and materialsAll animal experiments were carried out in accor- IntroductionGingival carcinoma often causes destruction of the jawbone (1-4). An understanding of the patterns and routes of carcinoma invasion into jaw-bone is essential in determining and deciding the appropriate surgical margin of jaw resection.Generally, bone resorption is considered to be mediated by osteoclasts. Recently the possibility of osteolysis by factors derived from the osteocytes or the tumor itself has also been suggested (5, 6). In addition, many recent reports have described enlargement of lacunae with proliferation of the tumor in the area of the bone adjacent to the tumor (7). It has also been suggested that this enlargement of osseous lacunae is closely related to the death of osteocytes (5,8,9) and is caused by osteolysis due to the death of osteocytes (8, 9). However, whether bone is resorbed not only by osteoclasts but also by other factors remains controversial (10-14). I. NR-S1 modelAnimals: Five-week-old male C3H/He mice (body weight 17-20g, n = 30, Charles River, Japan) were used. To minimize tissue injury due to tooth extraction, the mice were fed powdered food containing ß-aminopropionitrile (ß-APN, Sigma Chemical Co. U.S.A.) at a concentration of 0.4% for 5 days (18). The mice were then anesthetized with sodium pentobarbital (0.05mg/g), and the left maxillary incisor was extracted with the use of an exploratory needle and a mosquito forceps. Gauze and pressure were applied to the wound to promote hemostasis.Tumors: Transplantable NR-S1 tumor, which was derived from the buccal mucosa of a C3H mouse (19, 20)(National Institute of Radiological Sciences, Chiba, Japan) was used. The pathological features showed welldifferentiated squamous cell carcinoma. The NR-S1 tumor was serially passaged in the subcutaneous region of the mouse femur. Tumor transplantation into the extraction socketTwenty days after tumor transplantation, the subcutaneously proliferated NR-S1 tumor mass was harvested, washed with sterilized physiological saline solution, and minced into a piece measuring about 1mm 3 . One piece of this tumor was transplanted into the extraction socket of the left maxillary incisor of each animal. II. NB-1 modelAnimals: Four-week-old BALB/cANcrj female nude (nu/nu) mice(...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Experimental Transplantation of Carcinoma to Tooth Extraction Sockets: A bone invasion model

et al. 2003

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“…Prostaglandins, particularly PGE, are potent bone resorption agents in vitro (Dietrich et al 1975). The role of prostaglandins in certain states of pathologic bone resorption is supported by the bone mass sparing effect of nonsteroidal anti-inflammatory drug (NSAID) treatment of cancer metastases (Powles et al 1973, Galasko et al 1979, osteomyelitis Francis 1981, Rissing andBuxton 1986), and periodontal disease (Williams et al 1985). In experimental osteomyelitis, reduction in bone PGE was associated with decreased bone destruction in rabbits treated with sodium salicylate or ibuprofen (Rissing and Buxton 1986).…”

Section: Discussionmentioning

confidence: 99%

“…The E series prostaglandins are known to be potent bone resorption agents (Dietrich et al 1975), and large quantities of prostaglandin E2 are produced by bone in culture (Raisz et al 1979). Furthermore, treatment with inhibitors of prostaglandin synthesis has been associated with bone mass sparing in certain states of pathologic bone resorption, including cancer metastases (Powles et al 1973, Galasko et al 1979, osteomyelitis Francis 1981, Rissing andBuxton 1986), and periodontal disease (Williams et al 1985). Aspirin (acetylsalicylic acid) inhibits prostaglandin synthesis via irreversible acetylation of cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (Higgs et al 1984, Clissold 1986).…”

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confidence: 99%

Immobilization increases bone prostaglandin E: Effect of acetylsalicylic acid on disuse osteoporosis studied in dogs

Waters

Caywood

Trachte

et al. 1991

Acta Orthopaedica Scandinavica

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“…Both indomethacin and dichloromethane diphosphonate [C12C(PO3H2)2] reduce the bone calcium resorption produced by VX2 rabbit carcinoma in vitro (4,6) and the former is also effective in vivo (7). Cl2C(P03H2)2 is a potent inhibitor of osteoclastic bone resorption in vitro and in vivo (8,9).…”

mentioning

confidence: 99%

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

Doppelt¹,

Slovik²,

Neer³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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The VX2 carcinoma-bearing rabbit is an animal model for tumor-induced hypercalcemia, thought to be due to increased bone destruction effected by prostaglandin E2. The present experiments suggest that the pathophysiology of the hypercalcemia differs from that previously proposed. Tumor was transplanted intramuscularly into 2.5-to 3-kg male New Zealand White rabbits, which were conditioned to a 1.5% calcium diet and treated with daily subcutaneous injections of dichloromethane diphosphonate (10 mg-kg-'-day'), a potent inhibitor of bone resorption, or 0.9% NaCI (2 ml-kg'-day'1). The diphosphonate had no significant effect on plasma Ca2+ in either group. After day 31, half the animals of each group were fed a calcium-free diet. This normalized the plasma Ca2+ in each VX2-bearing rabbit within 3 to 4 days but had little effect in control rabbits. In a second series of experiments, VX2-bearing rabbits maintained on standard rabbit chow were treated for 11 days with parenteral indomethacin (30-60 mg/day) or 0.9% NaCl. Although indomethacin normalized the markedly elevated urinary excretion ofprostaglandin E2, both treatment groups became severely hypercalcemic. Dietary calcium restriction promptly restored to normal the plasma Ca2+ concentration. In a third series of experiments, rabbits were fed standard rabbit chow and treated with oral indomethacin (40 mg/ day) while control-rabbits were pair fed an identical chow. Transplantation of VX2 tumor into both groups caused hypercalcemia. We conclude that the hypercalcemia produced by this tumor strain is indomethacin resistant and dependent on an increase in gastrointestinal calcium absorption, not on skeletal calcium mobilization. Tumor-induced hypercalcemia is an aberration in calcium homeostasis caused by many different neoplasms (1). Hypercalcemia may be induced by direct bony invasion of tumor metastases. Some tumors, however, produce hypercalcemia without metastasizing to bone, presumably by secreting humoral substances such as parathyroid hormone, parathyroid hormone-like peptides, prostaglandins, osteoclast activitating factor, or vitamin D metabolites. Although the pathophysiology of the resultant hypercalcemia is poorly understood, tumor-induced hypercalcemia is thought to result primarily from bone resorption. This conclusion, however, is based primarily on in vitro evidence (1).The VX2 rabbit carcinoma produces fatal hypercalcemia by such a humoral mechanism, and the tumor secretes a substance, probably prostaglandin E2 (PGE2), that stimulates bone resorption in vitro (2-5). Both indomethacin and dichloromethane diphosphonate [C12C(PO3H2)2] reduce the bone calcium resorption produced by VX2 rabbit carcinoma in vitro (4, 6) and the former is also effective in vivo (7). Cl2C(P03H2)2 is a potent inhibitor of osteoclastic bone resorption in vitro and in vivo (8,9). It has been used successfully to reduce the excessive bone resorption caused by Paget disease (10), multiple myeloma (11), and parathyroid hormone (12).The original purpose of these experime...

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Timing of indomethacin in the control of prostaglandins, osteoclasts and bone destruction produced by VX2 carcinoma in rabbits

Cited by 22 publications

References 9 publications

Experimental Transplantation of Carcinoma to Tooth Extraction Sockets: A bone invasion model

Experimental Transplantation of Carcinoma to Tooth Extraction Sockets: A bone invasion model

Immobilization increases bone prostaglandin E: Effect of acetylsalicylic acid on disuse osteoporosis studied in dogs

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

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