Ultrastructural study of the effects of tranexamic acid and urokinase on metastasis of Lewis lung carcinoma

Tanaka, N.; Ogawa, Hisataka; Kinjo, Mitsuru; Kohga, Shin; Tanaka, Kenzö

doi:10.1038/bjc.1982.220

Cited by 25 publications

(27 citation statements)

References 9 publications

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“…As a result of rapid tumor growth in the lungs, the host animals died of bleeding in the pleural cavity within 3 weeks after tumor cell inoculation. 21,22,24,25) In the present experiment, mice were i.v. administered either a single dose or intermittent doses (every 7th day for a total of 4 doses, q7d×4) of DE-310, once daily times 5 doses (qd×5) of DX-8951f, or a single dose of CPA beginning on day 8.…”

Section: Compoundsmentioning

confidence: 90%

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DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

Kumazawa¹,

Ochi²

2004

Cancer Science

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he effect of current therapeutic agents appears when the agent acts on the target organ in the body. Since drug molecules that are distributed to organs that are not targeted may cause side effects, treatment is generally performed using a dose at which efficacy is obtained without unacceptable side effects. However, most antitumor chemotherapeutic agents show clinical effects only at doses that cause side effects such as digestive toxicity and myelosuppression. Therefore, in the development of new antitumor chemotherapeutic agents, it is important to discover compounds having a stronger antitumor effect and weaker toxicity compared with current antitumor chemotherapeutic agents. For example, CPT-11 was found to exhibit higher antitumor activity with less toxicity than camptothecin (CPT) and showed promising activity in clinical evaluation.1-8) However, it causes side effects such as severe watery diarrhea and there are marked inter-patient variations in both its effects and toxicity. 7, 9, 10) To obtain a more effective analogue with a lower toxicity, DX-8951f was designed.11) DX8951f is the most active inhibitor of topo I and tumor growth both in vitro and in vivo among the currently available CPT derivatives. [12][13][14] However, even with DX-8951f, there is no apparent increase in the selectivity to tumor tissue versus normal tissue and the half-life of the compound is relatively short (t 1/2 of 0.3 h mice). 15)The ideal antitumor drug would have high antitumor activity but no toxicity, i.e., it would be a compound for which efficacy and side effects are completely separate, but it is difficult to achieve this with low-molecular compounds, as the history of antitumor chemotherapeutics shows. Various approaches for superior targeting of antitumor compounds have been investigated by many researchers, and there have been trials of macromolecular pro-drugs. 16,17) Based on the results obtained from examinations of macromolecular conjugates using doxorubicin in DDS Institute, Ltd., we started to study drug delivery using a macromolecular carrier based on a DX-8951-conjugate, in order to enhance the antitumor effect and to reduce the hematological toxicity of DX-8951f.A novel macromolecular carrier system, based on the wellknown enhanced permeability and retention (EPR) effect, 18) was designed to target DX-8951 to tumors and to provide sustained release of DX-8951 in tumors. We conducted extensive optimization studies of the peptidyl spacer, molecular weight of the carrier, DX-8951 content and degree of carboxymenthylation.19) DE-310 is composed of DX-8951 and a biodegradable carrier, carboxymethyldextran polyalcohol (CM-Dex-PA), which are covalently linked by a peptidyl spacer (Gly-Gly-PheGly, GGFG).19) It has an average molecular weight of 340,000 (DX-8951 content: less than 8%, degree of carboxymethylation: ca. 0.3-0.4 per sugar residue). 19) In the present study, we examined the therapeutic efficacy of DE-310 against a variety of human and murine tumors in mice. Materials and MethodsCompounds. Fig. 1A), ...

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Section: Compoundsmentioning

confidence: 90%

“…Meth A was obtained from Hokkaido University, Sapporo. M5076 20) and 3LL 21,22) were obtained from the Japanese Foundation for Cancer Research, Tokyo. Meth A and M5076 were maintained by serial intraperitoneal passage in syngeneic mice.…”

Section: Compoundsmentioning

confidence: 99%

DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

Kumazawa¹,

Ochi²

2004

Cancer Science

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“…34) In some cases of lung cancer, the prognosis of patients with high expression of u-PA is reported to be significantly worse than that of patients with lower expression of u-PA. 35) Lymphatic metastasis of lung cancer is correlated with enhanced expression of u-PA. 36,37) It has been reported that the invasion and metastasis of LLC cells were inhibited by blocking the u-PA/ plasminogen system. [28][29][30] In addition, the c-Jun proto-oncogene product, which is a component of transcription factor AP-1, is also overexpressed in lung cancer patients with metastasis. 38,39) AP-1 is a major transcriptional enhancer for the transactivation of u-PA and u-PAR genes, expression of which is dependent on the activation of AP-1, although another factor, PEA3, binds to their promoter region.…”

Section: Discussionmentioning

confidence: 99%

“…4). Because blocking of the u-PA/plasminogen system is able to inhibit LLC cell invasion, [28][29][30] we next examined the effect of TAC-101 on the production of u-PA. As shown in Fig. 5A, two fibrinolytic bands were detected at approximately 100 kDa and at 55 kDa in the zymogram.…”

Section: )mentioning

confidence: 99%

TAC‐101 (4‐[3,5‐bis(trimethylsilyl)benzamido]benzoic acid) Inhibits Spontaneous Mediastinal Lymph Node Metastasis Produced by Orthotopic Implantation of Lewis Lung Carcinoma

Murakami

Yamaura

Suda

et al. 1999

Japanese Journal of Cancer Research

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Lung neoplasia is a major cause of death in cancer patients throughout the world. Diagnostic techniques and therapeutic modalities for lung cancer patients have been improved over the past decade; however, the overall death rate is still high. 1) Despite undergoing curative surgical treatment, many patients develop recurrent disease and most of such recurrent disease includes distant metastasis.2, 3) Therefore, controlling metastatic disease is one of the important problems that must be addressed in order to conquer lung neoplasia.Among the various clinicopathological factors, lymphatic metastasis is one of the most critical factors for the prognosis of lung cancer patients. [4][5][6] Although experimental models for lung cancer have been reported by several investigators, these models have included some important drawbacks, such as ectopic implantations and complicated procedures.7-9) Recently, we established a model of spontaneous lymphatic metastasis produced by orthotopic implantation of lung cancer cells.10) Direct implantation of Lewis lung carcinoma (LLC) admixed with "MATRIGEL" into the left lobe of the lung caused the formation of a solitary tumor followed by metastasis to the mediastinal lymph node. This model should be useful for investigating therapeutic approaches for lung cancer disease in preclinical studies.We have reported that 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid, TAC-101, abolished activating protein-1 (AP-1) binding to consensus DNA and inhibited the experimental liver metastasis of gastrointestinal tract cancer in animal models.11) AP-1 has been reported to be a major transcriptional enhancer for the expression of urokinase-type plasminogen activator, overexpression of which has been reported to be correlated with lymphatic metastasis of lung cancer. [12][13][14][15][16] In the present study, we investigated the effects of TAC-101 on the growth at the implantation site and the spontaneous lymphatic metastasis caused by the orthotopic implantation of LLC, and we examined its anti-metastatic mechanism of action in vitro. Since platinum agents have been used as standard treatment modalities for lung cancer, 1,17,18) combination therapy of TAC-101 and CDDP in the LLC model was also examined.

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“…Next, plasminogen is converted to active plasmin in a reaction that is catalyzed by PA (uPA or tPA) (11). It has been reported that the proteolytic activity of plasmin contributes to angiogenesis (1, 12) and invasion/metastasis (13)(14)(15). Reports also suggest that the morbidity and mortality of mice with Lewis lung carcinoma are due to excessive plasmin generation (16).…”

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confidence: 99%

Annexin II Dependent Mechanism of Breast Cancer Progression

Sharma¹

2009

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Ultrastructural study of the effects of tranexamic acid and urokinase on metastasis of Lewis lung carcinoma

Cited by 25 publications

References 9 publications

DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

DE‐310, a novel macromolecular carrier system for the camptothecin analog DX‐8951f: Potent antitumor activities in various murine tumor models

TAC‐101 (4‐[3,5‐bis(trimethylsilyl)benzamido]benzoic acid) Inhibits Spontaneous Mediastinal Lymph Node Metastasis Produced by Orthotopic Implantation of Lewis Lung Carcinoma

Annexin II Dependent Mechanism of Breast Cancer Progression

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