The Growth-Regulating Activity of Polyanions: A Theoretical Discussion of Their Place in the Intercellular Environment and their role in Cell Physiology

Regelson, William

doi:10.1016/s0065-230x(08)60389-9

Cited by 36 publications

(11 citation statements)

References 415 publications

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“…The extracellular matrix, which contains glycosarninoglycans such as hyaluronic acid, chondroitin sulfate, and heparan sulfate (Toole, 1976;Lindahl and Hook, 1978), has also been implicated to play an important role in cell-cell interactions, such as adhesiveness, cell migration, differentiation during morphogenesis, and anchorage to substrata (Regelson, 1968;Toole, 1976;Lindahl and Hook, 1978;Turley and Roth, 1979). The large size and high negative charge of these acidic carbohydrate polymers have been suggested as important characteristics of these molecules (Regelson.…”

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confidence: 99%

“…In addition to the naturally occurring acidic polymers, several synthetic acidic polymers have been shown to have profound effects on a variety of biological systems (Regelson, 1968). For example, the double-stranded homopolyribonucleotide pairs, poly I-poly C and poly A-poly U. are potent pharmacological agents in the induction of interferon production, immunopotentiation, and inhibition of tumor growth (see reviews by Regelson, 1968;Gresser, 1972;Stewart, 1979).…”

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“…For example, the double-stranded homopolyribonucleotide pairs, poly I-poly C and poly A-poly U. are potent pharmacological agents in the induction of interferon production, immunopotentiation, and inhibition of tumor growth (see reviews by Regelson, 1968;Gresser, 1972;Stewart, 1979). Their mechanism(s) of action have not been elucidated, but some insight may be provided from the observations that poly I apoly C, poly A apoly U, and dextran sulfate appear to be capable of acting as mitogens for murine T and B lymphocytes in vitro (Riihl et al, 1974;Johnson and Han, 1974;Diamantstein et al, 1974;Diamantstein and Blit stein-Willinger, 1975).…”

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Mitogenesis in normal human fibroblasts by polyinosinic · polycytidylic acid and other synthetic acidic polymers: Enhancement of action by glucocorticoids

Barrack

Hollenberg

1981

Journal Cellular Physiology

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The ability of specific synthetic polyelectrolytes to act as mitogens for quiescent normal human fibroblasts in cultures is described. Of several acidic polymers tested, polyinosinic acid .polycytidylic acid (poly I.poly C) and dextran sulfate were the most effective in stimulating 3H]thymidine incorporation (2-to 10-fold). The concentration for a half-maximal effect (ED50) was 0.4 microgram/ml (0.8 nM) for poly I.poly C, and 1.7 microgram/ml (3.4 nM) for dextran sulfate. Single-stranded polyinosinic acid or polycytidylic acid had no effect. The time course of stimulation of DNA synthesis by these acidic polymers was similar to that for naturally occurring mitogens such as epidermal growth factor, beginning at about 18 hours and reaching a maximum rate 26 to 30 hours after the addition of polymer. Glucocorticoids that have an 11-beta hydroxyl group (e.g., dexamethasone) had no effect on DNA synthesis alone, but enhanced several-fold the mitogenic activity of poly I.poly C or dextran sulfate; the ED50 for dexamethasone was 0.75 ng/ml (1.9 nM). Glucocorticoids with an 11-keto group were inactive in this respect. The labeling index following treatment of cultures with poly I.poly C and dexamethasone was 14%, compared with a labeling index of 25% following stimulation by fetal calf serum. The extent of stimulation of DNA synthesis by poly I.poly C and dexamethasone was comparable to that induced by epidermal growth factor. It appears that both the poly I.poly C and dexamethasone are required for only a short period of time (approximately 3 hours) in order to produce maximal stimulation of DNA synthesis 30 hours later.

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Mitogenesis in normal human fibroblasts by polyinosinic · polycytidylic acid and other synthetic acidic polymers: Enhancement of action by glucocorticoids

Barrack

Hollenberg

1981

Journal Cellular Physiology

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“…Many polymers can chelate divalent cations, and alterations of calcium flux may indeed be important in their antitumor activity [13]. Chelation of calcium could result in hypercalciuria but might be expected to result in hypocalcemia rather than hypercalcemia.…”

Section: Discussionmentioning

confidence: 99%

Phase I trial of a 5-day course of carbetimer

et al. 1990

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Carbetimer (carboxyimamidate) is a low molecular weight derivative of ethylene/maleic anhydride polymer. This compound has demonstrated antitumor activity against several animal models with a daily x 5 schedule appearing most effective. A phase I clinical study of the daily x 5 schedule repeated every 28 days was therefore performed. Forty-one evaluable patients received 66 evaluable cycles of Carbetimer at daily doses ranging from 100-11000 mg/m 2. Hypercalcemia was the dose limiting toxicity with both patients at the 11000 mg/m 2 daily dose level and one patient who received 6 cycles of drug at the 4200 mg/m 2 dose level developing severe hypercalcemia not explained by the underlying malignancy. Mild nausea, concentration and rate dependent arm pain at the site of infusion, proteinuria, and coagulopathy were also seen. Calcium balance studies revealed hypercalciuria, suggesting increased mobilization of calcium rather than renal retention. In vitro coagulation studies revealed concentration dependent prolongation of the partial thromboplastin time and thrombin time. No complete or partial responses were seen. However mixed response or biochemical response (reduction in serum lactic dehydrogenase) were seen in 5 patients with melanoma or renal cancer. Due to unacceptable toxicity at the 11000 mg/m 2 daily dose level, Carbetimer 8500 mg/m 2 is the recommended dose for a 5-day treatment schedule every 28 days. Special attention should be directed toward possible activity against melanoma and renal cancer.

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“…Due to their capability of enzymatic and mytotic inhibition poly phosphates present experimental anti-tumor activity [18,19]. In order to find out the type of enzymatic action involved in the hydro lysis of condensed phosphates by tumor tissue and to establish the possible relationships with other cellular metabolic processes, the present experimental study has been undertaken.…”

Section: Introductionmentioning

confidence: 99%

The Enzymatic Hydrolysis of Polyphosphates in Tumor Tissue Its Influence on the in vivo Uptake

Anghileri¹,

Miller²

1971

Enzyme

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The in vitro hydrolysis of polyphosphates by tissues from tumor-bearing animals has been studied. The analysis of the hydrolytic products indicates that the molecular break down occurs at the level of the terminal phosphate groups. The Mg++-dependent pyrophosphatase activity of tumor appears considerably diminished. Besides the fact that there is a relationship between hydrolysis and in vivo uptake with the phosphatase activity of the tissue, it seems possible that other mechanisms (as calcium-polyphosphate interaction) are involved in this uptake.

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The Growth-Regulating Activity of Polyanions: A Theoretical Discussion of Their Place in the Intercellular Environment and their role in Cell Physiology

Cited by 36 publications

References 415 publications

Mitogenesis in normal human fibroblasts by polyinosinic · polycytidylic acid and other synthetic acidic polymers: Enhancement of action by glucocorticoids

Mitogenesis in normal human fibroblasts by polyinosinic · polycytidylic acid and other synthetic acidic polymers: Enhancement of action by glucocorticoids

Phase I trial of a 5-day course of carbetimer

The Enzymatic Hydrolysis of Polyphosphates in Tumor Tissue Its Influence on the in vivo Uptake

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