Enzyme Activity in Invasive Tumors of Human Breast and Colon

Bosmann, H.Bruce; Hall, Timothy C.

doi:10.1073/pnas.71.5.1833

Cited by 173 publications

(74 citation statements)

References 26 publications

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“…Enhanced proteolytic activity has been correlated with the malignant state in vivo where it has been demonstrated that increased levels of proteolytic enzymes are found in the tissues as well as the plasma and other fluids of many species of animals exhibiting a variety of malignant tumors (6,20, 472 …”

Section: Introductionmentioning

confidence: 99%

“…It appears from these studies that the enzymatic composition of tumor cells and tumor interstitial fluid is shifted to favor the hydrolysis of polypeptides, and it has been suggested that these hydrolytic enzymes are involved in the invasiveness of malignant cells (6,20,56).…”

mentioning

confidence: 99%

“…The PA activity from hamster SV40 cells fractionated the same way as that of RSV-CEF. These results suggest that a protease that is dramatically enhanced upon malignant transformation is associated with "plasma membrane-like" elements of the cell and may serve as an intrinsic modifier of cell surface proteins after malignant transformation.Enhanced proteolytic activity has been correlated with the malignant state in vivo where it has been demonstrated that increased levels of proteolytic enzymes are found in the tissues as well as the plasma and other fluids of many species of animals exhibiting a variety of malignant tumors (6,20, 472 …”

mentioning

confidence: 99%

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Association of a protease (plasminogen activator) with a specific membrane fraction isolated from transformed cells.

Quigley¹

1976

The Journal of Cell Biology

154

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The intracellular distribution of a specific protease, plasminogen activator (P,~/), has been examined in Rous sarcoma virus-transformed chick embryo fibroblasts (RSV-CEF). Cellular homogenates were fractionated by differential centrifugation followed by sucrose gradient centrifugation. The activities and the percent distribution of a series of marker enzymes, specific for different subcellular organelles, were compared to those of PA. Normal CEF have been similarly fractionated and the relatively low amount of PA activity present in these cells has been analyzed in terms of its subcellular distribution.A membrane fraction was isolated from the RSV-CEF that contained the bulk of the PA activity and less than 8% of the total cellular protein. The specific activity of the PA in this fraction is 40-fold higher than that of a comparable fraction isolated from companion cultures of normal cells. This fraction contains little or no nuclear and cytoplasmic material and is contaminated only to a relatively small degree with mitochondria, lysosomes, and endoplasmic reticulum. Significant amounts of a putative Golgi membrane marker are present in this fraction. The relatively high specific activities of Na +,K+-ATPase, 5'-nucleotidase, and [aH]fucose indicate that the fraction is enriched in surface membrane. Further purification of the fraction by equilibrium centrifugation on shallow sucrose gradients reduces further the contaminating activities and results in a PA distribution that closely parallels the distribution of the membrane enzyme, 5'-nucleotidase. PA was not released from its membrane association by hypotonic and hypertonic extraction and ultrasonication, while granule-bound enzymes were released by these treatments. The PA activity from hamster SV40 cells fractionated the same way as that of RSV-CEF. These results suggest that a protease that is dramatically enhanced upon malignant transformation is associated with "plasma membrane-like" elements of the cell and may serve as an intrinsic modifier of cell surface proteins after malignant transformation.Enhanced proteolytic activity has been correlated with the malignant state in vivo where it has been demonstrated that increased levels of proteolytic enzymes are found in the tissues as well as the plasma and other fluids of many species of animals exhibiting a variety of malignant tumors (6,20, 472

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Association of a protease (plasminogen activator) with a specific membrane fraction isolated from transformed cells.

Quigley¹

1976

The Journal of Cell Biology

154

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“…Thus, although the original claim of Schnebli and Burger (1972) that the growth-inhibitory effects of protease inhibitors are directed selectively against malignant tumour cells, has not beeni suibstantiated (Hynes, 1 976;Schuiebli, 1975) nevertheless, inhibition of maligniant cell growth by protease inhibitors lends to the view (Bosmann and Hall; Easty and Easty, 1976; Hynes, 1976;Schnebli, 1975;Sylven, 1967) that tumour cell proteases potentiate the growth of malignant tumours. However, evaluation of aprotinin as an anti-tumour agent in vivo by various authors has produced variable results (Back et al, 1966;Back and Steger, 1976;Cliffton and Agostino, 1964;Giraldi et al, 1977;Latner et al, 1974;Thomson et al, 1977).…”

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confidence: 99%

Endocytosis of the antiprotease aprotinin by Landschütz ascites carcinoma cells and its effects in vitro and in vivo

Thomson¹,

Tweedie²,

Pugh-Humphreys³

et al. 1978

Br J Cancer

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Summary.-Aprotinin was bound and endocytosed by Landschutz ascites carcinoma (LAC) cells in vitro. Addition of the antiprotease to cultures of these cells led to a dosedependent growth-inhibitory and cytotoxic effect. In mice inoculated with LAC cells and treated with aprotinin there was a transient reduction in both the number and concentration of recovered ascites cells during the early phase of tumour growth. This was accompanied by a temporary increase in the proportion of peritoneal phagocytes (mononuclear phagocytes and polymorphonuclear leucocytes) relative to carcinoma cells. However, the number and concentration of ascites cells eventually achieved was comparable in saline and aprotinin-treated animals.

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“…4 It is known that β-galactosidase activity is enhanced in some cancer cell lines, such as ovarian, 5 breast, 6 colon, 6 and larynx 7 cancers and gliomas. 8 Utilizing this characteristic, Asanuma et al developed a fluorescence probe that is transformable into a fluorescent dye by β-galactosidase and applied it to the visualization of small peritoneal metastases in mouse models of ovarian cancer.…”

mentioning

confidence: 99%

Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy

Doura

Takahashi

Ogra

et al. 2017

ACS Med. Chem. Lett.

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Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-βGal-1 without a linker. Therefore, CA4-βGal-2 can serve as a platform for the design and manufacture of prodrugs for ovarian cancer PMT. KEYWORDS: Antitumor agent, prodrug monotherapy, ovarian cancer, tubulin polymerization inhibitor, β-galactosidase, combretastatin A4 O varian cancer is called a "silent killer", and its late diagnosis reduces the overall cure rate.1 Metastasis of ovarian cancer cells to the peritoneal cavity occurs easily because no anatomical barrier exists between them.2 Chemotherapy for stage 3 patients (in whom ovarian cancer cells have metastasized to the abdomen) revealed that intraperitoneal delivery of cisplatin and paclitaxel is more effective than intravenous delivery of those drugs. However, the intraperitoneal delivery method causes more side effects than the intravenous delivery method.3 This indicates that chemotherapy for advanced-stage ovarian cancer patients requires antitumor agents that exhibit selective cytotoxicity to cancer cells.In prodrug monotherapy (PMT), a nontoxic prodrug is administered, which releases a cytotoxic drug in response to enzymatic activity enhanced in tumor tissues, realizing cancer cell selective chemotherapy. 4 It is known that β-galactosidase activity is enhanced in some cancer cell lines, such as ovarian, 5 breast, 6 colon, 6 and larynx 7 cancers and gliomas. 8 Utilizing this characteristic, Asanuma et al. developed a fluorescence probe that is transformable into a fluorescent dye by β-galactosidase and applied it to the visualization of small peritoneal metastases in mouse models of ovarian cancer.9 Based on this result, we hypothesized that noncytotoxic molecules that are transformed into cytotoxic molecules by β-galactosidase are suitable prodrugs for ovarian cancer PMT.We focused on combretastatin A4 (CA4), a potent tubulin polymerization inhibitor, because microtubule disrupting agents, such as paclitaxel, are used for ovarian cancer chemotherapy. CA4 is a natural product isolated from the bark of the African willow tree Combretum caf f rum. 10Structure−activity relationship studies of CA4 revealed that the three methoxy substituents on ring A, the cis-stilbene moiety, and hydrogen bond donors, such as the hydroxy group on ring B, are necessary for CA4 to exert potent cytotoxicity (Figure 1a). 11 Based on this knowledge, we speculated that the cytotoxicity of CA4 would be weakened by substituting a β-

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Enzyme Activity in Invasive Tumors of Human Breast and Colon

Cited by 173 publications

References 26 publications

Association of a protease (plasminogen activator) with a specific membrane fraction isolated from transformed cells.

Association of a protease (plasminogen activator) with a specific membrane fraction isolated from transformed cells.

Endocytosis of the antiprotease aprotinin by Landschütz ascites carcinoma cells and its effects in vitro and in vivo

Combretastatin A4-β-Galactosyl Conjugates for Ovarian Cancer Prodrug Monotherapy

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