Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Tumor Immunology: New Perspectives
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
[Cancer Research 59, 3919-3922, August 1, 1999]
© 1999 American Association for Cancer Research
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sasaki, H.
Right arrow Articles by Fukushima, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sasaki, H.
Right arrow Articles by Fukushima, M.
[Cancer Research 59, 3919-3922, August 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Antitumor Activity of 13,14-Dihydro-15-deoxy-{Delta}7-prostaglandin-A1-methyl Ester Integrated into Lipid Microspheres against Human Ovarian Carcinoma Cells Resistant to Cisplatin in Vivo1

Hiroshi Sasaki2, Shigeki Niimi, Minoru Akiyama, Tadao Tanaka, Atsuo Hazato, Seiji Kurozumi, Shoji Fukushima and Masanori Fukushima

Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461 [H. S., S. N., T. T.]; Department of Obstetrics and Gynecology, Shiga University of Medical Science, Ohtu 520-21 [M. A.]; Department of Pharmacology, Kobe Gakuin University, Kobe 651-2113 [A. H., S. K., S. F.]; and Department of Internal Medicine, Aichi Cancer Center, Nagoya 464-0021 [M. F.], Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
One of the {Delta}7-prostaglandin A1 derivatives with unique antitumor activities, 13,14-dihydro-15-deoxy-{Delta}7-prostaglandin-A1-methyl ester, was integrated into lipid microspheres (Lipo-TEI9826) and examined for its antitumor effect in vitro and in vivo. The in vitro relative resistance of human ovarian cancer, A2780CP, to cisplatin (CDDP) and Lipo-TEI9826 was 27.3 and 2.0, respectively, compared with A2780, the parent cell line of A2780CP. In in vivo experiments, when A2780CP and the parent cell line A2780 were inoculated into nude mice, A2780CP grew two times more rapidly than did A2780. The growth of A2780CP tumor was not suppressed by CDDP, whereas that of the A2780 tumor was significantly suppressed. Nevertheless, the growth of both the A2780 and the A2780CP inoculated tumors was significantly inhibited by treatment with Lipo-TEI9826 at any time after the initial treatment, compared with the lipid microspheres only. These results show that Lipo-TEI9826 may be an effective antitumor agent and capable of overcoming CDDP resistance.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The series of PGs3 A and J, members of a unique category of PG, the cyclopentenone PGs, exhibit potent antitumor, antiviral, and differentiation activities, including activities affecting cell cycle arrest at the G1 phase (2, 3, 4, 5) . Recent reports have unveiled molecular mechanisms of such PGs and their physiological roles in adipogenesis (6 , 7) . One of the antitumor mechanisms of such PGs is an induction of p21, which does not depend on p53, resulting in G1 arrest in tumor cells, i.e., the compound might mimic p53 in the cells lacking p53 (8, 9, 10, 11) . In the previous study, we demonstrated in vitro antitumor activity of {Delta}12-PGJ2 and {Delta}7-PGA1 against a human ovarian cancer cell line (12) . These PGs displayed very little cross-resistance to either CDDP or doxorubicin. Although {Delta}7-PGA1 is active in vivo in various tumor systems (4 , 13 , 14) , the half-life of this type of PG in sera is very short, because it is converted to an inactive form (15) . These facts prompted us to examine the antitumor activity of 13,14-dihydro-15-deoxy-{Delta}7-PGA1 which is stable in sera as {Delta}12-PGJ2 (16 , 17) . TEI9826, an analogue of {Delta}12-PGJ2, has a novel structure and exhibits unique antitumor profiles by the COMPARE program with 38 human tumor strains in vitro (18) . Here we report the antitumor activity of lipid microsphere-integrated TEI9826 in vitro and in vivo with human ovarian cancer cells both sensitive and resistant to CDDP.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Lines.
Two cell lines derived from human ovarian adenocarcinoma were used in this study. A2780 cells and A2780CP cells were kindly provided by Dr. T. C. Hamilton (Fox Chase Cancer Center, Philadelphia, PA). The two cell lines were grown at 37°C in RPMI 1640 supplemented with 10% FCS, 2 mM L-glutamine, 100 units/ml of penicillin, and 100 µg/ml of streptomycin and were maintained in a humidified atmosphere of 5% CO2.

Chemicals.
Fetal bovine serum was purchased from FLOW Laboratories (North Ryde, Australia). CDDP (Briplatin; 10 mg/ml) was obtained from Bristol-Myers Squibb Co. Ltd. (Tokyo, Japan). TEI9826, the chemical structure of which is as shown in Fig. 1Citation , was the product of Teijin Ltd. (Tokyo, Japan). TEI9826 was dissolved at a concentration of 10 mg/ml in 99.9% ethanol and stored in -20°C. The stock solution was diluted with fresh RPMI 1640 at the appropriate concentrations just before use in vitro. Each equivalent solvent solution was added to control dishes such that the final concentration of ethanol was <0.56% (v/v) in all experiments on PGs. 1-Chloro-2,4-dinitrobenzene was obtained from Aldrich Chemical Co. and was diluted before use in vitro. Lipid microsphere-integrated TEI9826 was prepared as described below. Purified egg lecithin (PL100E) was purchased from QP Co. Ltd. (Tokyo, Japan); the content of phosphatidyl choline is ~80%, and the content of phosphatidyl ethanolamine is ~20%. This lecithin is suitable for clinical use. Purified, clinical grade soybean oil was purchased from Nacalai Tesque Co. Ltd. (Kyoto, Japan) for use in the formulation of fatty lipid emulsion.



View larger version (6K):
[in this window]
[in a new window]
  		Fig. 1. Chemical structure of TEI9826.

 
Preparation of Lipid Microsphere-integrated TEI9826 (Lipo-TEI9826).
We have been examining Lipid microspheres as a dosage formulation for antitumor PG (14 , 16 , 18, 19, 20) , because these PGs are highly lipophilic substances and cannot be administered in aqueous solutions. TEI9826 is a liquid at -20°C and is miscible at any ratio with vegetable oils such as soy bean oils, which is the oil phase of fatty-lipid emulsion in clinical use. Therefore, preparation of lipid emulsion containing TEI9826 is very easy by the procedure for commonly producing fatty lipid emulsion in laboratory scale and industrial scale. Egg yolk lecithin (1.2 g) was dispersed in injection-grade water (85.8 g) containing glycerin (2.5 g) at 60°C. The mixture (clear oily liquid) of TEI9826 (0.5 g) and soybean oil (9.5 g) was introduced into the lecithin dispersion solution (total volume, 100 ml) and emulsified well with a high-pressure homogenizer (Microfluidizer) at a pressure of 20,000 psi. Oil droplet size was measured with a dynamic light scattering particle sizer (Zeta-Plus; Brookhaven Instrument Co.) and was ~180 nm. TEI9826 content in the formulation was 5.0 mg/ml. Lipo-TEI9826 is freely soluble in 5% glucose and stable for years at 4°C. Control lipid microspheres were prepared by the same method without TEI9826.

Measurement of Growth Inhibition.
The two cell lines in log-phase, grown as a monolayer in 100-cm2 culture flasks, were trypsinized and suspended in 0.2 ml of the complete growth medium. The suspended cells were seeded (1.5 x 103 cells for A2780 and A2780CP) into each well of a 96-well tissue culture plate (Costar, Cambridge, MA) and incubated in a humidified atmosphere of 5% CO2 at 37°C for 24 h. Then, a 10-µl quantity of medium containing various concentrations of TEI9826 (0.1–10 µg/ml), Lipo-TEI9826 (0.1–10 µg/ml), control lipid microspheres, and CDDP (0.024–4 µg/ml) was put into each well, and the plate was incubated for 96 h at 37°C in a CO2 incubator. The number of cells adhering to the bottom of each well was calculated by a modified indirect colorimetric method with an automatic photometer (Dynatech Laboratories, Inc., Tokyo, Japan) as described before (21) . Simply, the medium was discarded, and the adherent cells were fixed with methanol for 2 min, then left at room temperature. Each well was filled with 200 µl of 3% hydrochloric acid with the dissolved dye. The absorbance of the hydrochloric acid solution was measured with an automatic photometer (Dynatech Laboratories, Inc.) at 660 nm. Growth inhibition was calculated by:

A660 (treated cells) indicates the absorption intensity of a methylene blue solution obtained from cells treated with a drug. A660 (control cells) indicates a methylene blue solution obtained from the control cells (4.8 x 104 cells). All experiments were performed in triplicates, and each point was obtained from three to four separate experiments. IC50s, implying the concentrations necessary for 50% inhibition of cell growth, were calculated from the growth inhibition curves.

Nude Mice.
Female nude mice (BALB/c, nu/nu, ~5 weeks of age) were obtained from Japan Clea laboratories (Tokyo, Japan) and maintained in a pathogen-free environment. The mice were cared for daily, and body weights were recorded to monitor the side effects of the drugs. When necessary, the animals were killed and dissected, and the tumor tissues were fixed in formalin for histological examinations. Distant metastases were not observed during the experimental periods.

In Vivo Treatment.
To examine the in vivo antitumor activities of CDDP and PGs on the growth of both the A2780 and A2780CP tumors, 2 x 106 cells of each tumor type were separately inoculated s.c. into the nude mice. After a tumor grew to about 5 mm in diameter, 80 mg/kg/day Lipo-TEI9826 was administered i.p. three times a week for 2 weeks, up to six times. Ten mice were divided into two groups: five mice treated with 80 mg/kg/day of Lipo-TEI9826 and another five with 5% glucose aqua including the vehicle, i.e., lipid microspheres only as a control group. Tumor sizes (both longitudinal and latitudinal width) of the two groups were measured with a scale.

To investigate CDDP resistance of A2780 tumors in vivo, 3.5 mg/body weight (kg)/day of CDDP was administered i.p. once a week for 3 weeks into five nude mice bearing A2780CP and another five bearing A2780 cells after the size of every tumor of both A2780 and A2780CP cells became ~5 mm in diameter. As a control group, saline alone was administered once every week for 3 weeks to five other mice.

Statistical Analysis.
Results in the figures, expressed as the mean ± SD, were analyzed using Student’s t test, and differences were considered significant when Ps were <0.05.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
The Antitumor Activities of TEI9826, Lipo-TEI9826, Lipid Microspheres, and CDDP on A2780 and A2780CP Cell Growth in Vitro.
Fig. 2Citation shows growth inhibition curves of A2780 and A2780CP cells treated with CDDP, TEI9826, Lipo-TEI9826, and control lipid microspheres. IC50s of A2780 and A2780CP were 0.072 and 1.7 µg/ml for CDDP, 0.70 and 1.4 µg/ml for TEI9826, and 0.70 and 1.4 µg/ml for Lipo-TEI9826, respectively. Lipid microspheres alone exerted little growth inhibition on either 2780 cells or 2780CP cells. These results demonstrate that Lipo-TEI9826 inhibited the growth of both 2780 and 2780CP cells to about the same extent as TEI9826 did in vitro.



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 2. Growth inhibition curves of A2780 cells (A) and A2780CP (B) cells treated with CDDP, TEI9826, Lipo-TEI9826, or control lipid microspheres alone. •, cells treated with CDDP; {triangleup}, treated with TEI9826; {blacksquare}, treated with Lipo-TEI9826; {circ}, treated with control lipid microspheres alone. The antitumor activities of the drugs were defined with IC50s calculated from growth inhibition curves, which were obtained by an indirect colorimetric method.

 
Growth Inhibition of Human Ovarian Carcinoma Cells, A2780, and A2780CP, Inoculated s.c. into Nude Mice Treated with CDDP.
Fig. 3Citation demonstrates the growth inhibition of A2780 and A2780CP tumors treated with CDDP. The doubling time for tumors of A2780 and A2780CP were roughly 6 and 3 days, respectively. CDDP significantly inhibited the growth of the A2780 tumor, compared with that of the A2780CP tumor. On the contrary, no significant growth inhibition was shown for either A2780 treated with saline or A2780CP treated with saline or CDDP.



View larger version (19K):
[in this window]
[in a new window]
  		Fig. 3. Growth inhibition curves of A2780 and A2780CP cells inoculated s.c. into nude mice treated with 3.5 mg/kg of CDDP or saline once a week for 3 weeks. {circ}, A2780 cells treated with saline; •, A2780 cells treated with CDDP; {triangleup}, A2780CP cells treated with saline; {blacktriangleup}, A2780CP cells treated with CDDP. Bars, SD.

 
Effect of Lipo-TEI9826 on Growth Inhibition of A2780 and A2780CP Tumors Inoculated s.c. into Nude Mice in Vivo.
Fig. 4ACitation shows growth curves of the A2780 tumor treated with Lipo-TEI9826 or vehicle alone (control). There was a significant difference in growth inhibition between the Lipo-TEI9826 treated and control groups. Fig. 4BCitation shows growth inhibition curves for A2780CP tumor cells treated with Lipo-TEI9826 or control. Lipo-TEI9826 significantly inhibited the growth of the CDDP-resistant tumor, whereas lipid microspheres did not.



View larger version (13K):
[in this window]
[in a new window]
  		Fig. 4. Tumor volume of A2780 (A) and A2780CP (B) cells inoculated into nude mice. {circ} and {triangleup}, treated with control lipid microspheres alone; • and {blacktriangleup}, treated with Lipo-TEI9826 (80 mg/kg three times/week, i.p., for a total of six times). Nude mice were treated as described in "Materials and Methods." A, Lipo-TEI9826 significantly inhibited the tumor growth of A2780 cells inoculated into nude mice, compared with the vehicle. Bars, SD. B, treatment with TEI-9826 resulted in the significant inhibition of tumor growth of A2780CP cells inoculated into nude mice, compared with treatment with control lipid microspheres alone. Bars, SD.

 
Effect of Lipo-TEI9826 Treatment on Body Weights of Tumor-bearing Nude Mice.
The changes in body weights of nude mice bearing the A2780 tumor treated with Lipo-TEI9826 or vehicle were compared with those of nude mice bearing the A2780CP tumor treated with Lipo-TEI9826 or vehicle. Body weights of Lipo-TEI9826 treated mice did not significantly change during the experiments. Body weights of nude mice bearing the A2780 tumor and treated with vehicle increased gradually to the 10th day, followed by no significant changes from the 10th to 15th day. Body weight gains of nude mice bearing the A2780CP tumor were observed up to the 15th day unrelated to treatment, and there were no significant differences in weight gains between the experimental group and the controls.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
A novel species of antitumor agent, TEI9826, was demonstrated to suppress CDDP-resistant human ovarian cancer cells inoculated into nude mice s.c. The human ovarian cancer cell line A2780CP is 24 times more resistant to CDDP than is its wild-type A2780 in vitro. When A2780CP cells were inoculated into nude mice s.c., the developing tumor grew two times more rapidly than did that of the wild type in terms of doubling time, and CDDP could not suppress the tumor growth under the conditions where the drug is effective against the wild type. TEI9826 effectively inhibited proliferation of the CDDP-resistant cells in vitro and showed very little cross-resistance to CDDP (IC50s were 0.7 µg/ml for A2780 and 1.4 µg/ml for A2780CP). TEI9826 showed significant suppression of tumor growth under the conditions of our study, with the drugs administered in this dose and schedule. The Lipo-TEI9826 effects on the cell cycle are dependent on its concentration. At the inhibitory concentration 50% (IC50) of Lipo-TEI9826, cells accumulate in G1 phase. This effect is partially reversible, because the time dependency occurred when the exposure time of Lipo-TEI9826 was prolonged (4) . At an IC90 level of Lipo-TEI9826, cells accumulate in G2-M phases and then irreversibly begin cell death mechanisms (4) . When the tumors transplanted in nude mice were removed after treatment with Lipo-TEI9826 and then analyzed, fractions in the cell cycle, both G1-phase cell accumulation and decrease in S-phase cell fraction, were found (4) . This suggests that the in vivo mechanism of this compound may be cytostatic via G1 arrest in the cell cycle (4) . In this experimental condition, no toxicity was found, whereas weight gain in the experimental mice during the observation period was slightly lower than that observed in the controls (statistically not significant). These results strongly suggest that TEI9826 may overcome CDDP resistance at least partly in some tumors. Furthermore, {Delta}12-PGJ2, a physiological alkylidene-cyclopentenone PG, is reported to display synergistic activity with CDDP in vitro in various cell lines, such as Tamoxifen-resistant 289 TAM6 melanoma cells (22 , 23) and the colon cancer cell lines, LS174T and COLO201 (24) . Although we did not examine the synergism of TEI9826 with CDDP, it should be confirmed by in vivo experiments in the future with the above-mentioned cell lines. We reported before that 2008DDP cells, which showed increased intracellular GSH levels as a major mechanism for their resistance to CDDP, had some cross-resistance to PGs (12) . This cross-resistance might be caused by delayed incorporation of PGs into nuclei. On the contrary, however, Lipo-TEI9826 inhibited the growth of both A2780CP and A2780 human ovarian cancer cells, despite increased intracellular GSH levels in A2780CP cells, compared with A2780 cells (25) . These results suggest that GSH-related detoxification mechanisms might not necessarily have an important role in the acquired resistance to PG in these cell lines. In contrast to intracellular GSH levels, MRP/GS-X pump overexpression is identified as a candidate for conferring resistance to both CDDP and {Delta}7-PGA1 in HL60/R-cp cells, and very recently it was shown that KT-5908, a specific inhibitor of the MRP/GS-X pump, dose dependently enhanced the cellular sensitivity of the cells to {Delta}7-PGA1 methyl ester, where cell growth inhibition was linked with cell cycle arrest in G1 phase (26 , 27) . Because TEI9826 showed a very unique profile of tumor cell growth inhibition for a panel of 38 human cancer cell lines and the COMPARE program for this PG indicated no similarity to other known antitumor agents (18) , it would be quite reasonable to develop this compound toward clinical use.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by a grant-in-aid for cancer research from the Ministry of Health and Welfare, and the results were presented in part at the 87th annual meeting of the American Association for Cancer Research in 1996 (1) . Back

2 To whom requests for reprints should be addressed, at Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi Minato-ku, Tokyo 105-8461, Japan. Back

3 The abbreviations used are: PG, prostaglandin; CDDP, cisplatin; TEI9826, 13,14-dihydro-15-deoxy-{Delta}7-PGA1 methyl ester; GSH, glutathione. Back

Received 4/16/99. Accepted 6/30/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Akiyama M., Sasaki H., Fukushima S., Suzuki M., Fukushima M., Terashima Y., Tanaka T. In vivo antitumor activity of 13,14-dihydro-15-deoxy-{Delta}7-PGA1-methylester (TEI-9826) to human ovarian cancer cells resistant to cisplatin. Proc. Am. Assoc. Cancer Res., 37: 318 1996.
  2. Fukushima M. PGJ2-antitumor and anti-viral activities and mechanisms involved. Ecosanoids, 3: 189-199, 1990.
  3. Fukushima M. Biological activities and mechanisms of action of PGJ2 and related compounds: an update. Prostaglandins Leukotrienes Essent. Fatty Acids, 47: 1-12, 1992.[Medline]
  4. Fukushima M., Sasaki H., Fukushima S. PGJ2 and related compounds. Mode of action in G1 arrest and preclinical results. Ann. NY Acad. Sci., 744: 161-165, 1994.[Medline]
  5. Suzuki M., Mori M., Niwa T., Hirata R., Furuta K., Ishikawa T., Noyori R. Chemical implications for antitumor and antiviral prostaglandins: reaction of {Delta}7-PGA1 and PGA1-methylesters with thiols. J. Am. Chem. Sci., 119: 2376-2385, 1997.
  6. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M. 15-Deoxy-{Delta}12,14-PGJ2 is a ligand for the adipocyte determination factor PPAR{Delta}. Cell, 83: 803-812, 1995.[Medline]
  7. Kliewer S. A., Lenhard J. M., Willson T. M., Patel T., Morris D. C., Lehman J. M. A PGJ2 metabolite binds peroxisome proliferator-activated receptor {Delta} and promotes adipocyte differentiation. Cell, 83: 813-819, 1995.[Medline]
  8. Gorospe M., Holbrook N. J. Role of p21 in prostaglandin A2-mediated cellular arrest and death. Cancer Res., 56: 475-479, 1996.[Abstract/Free Full Text]
  9. Gorospe M., Liu Y., Xu Q., Chrest F. J., Holbrook N. J. Inhibition of G1 cyclin-dependent kinase activity during growth arrest of human breast carcinoma cells by prostaglandin A2. Mol. Cell. Biol., 16: 762-770, 1996.[Abstract]
  10. Ohtani-Fujita N., Minami S., Mimaki S., Dao S., Sakai T. p53-independent activation of the gadd45 promoter by {Delta}12-PGJ2. Biochem. Biophys. Res. Commun., 251: 648-652, 1998.[Medline]
  11. Akimaru K., Nakanishi M., Suzuki M., Furuta K., Noyori R., Ishikawa T. Cell growth inhibition by antitumor prostaglandin and its modulation by MRP/GS-X pump Honnet al eds. . Eicosanoids and Other Bioactive Lipids in Cancer Inflammation and Radiation Injury 3, : Plenum Publishing Corp. New York 1997.
  12. Sasaki H., Takada K., Terashima Y., Ekimoto R., Takahashi K., Tsuruo T., Fukushima M. Human ovarian cancer cell lines resistant to cisplatin, doxorubicin, and L-phenylalanine mustard are sensitive to {Delta}7-PGA1 and {Delta}12-PGJ2. Gynecol. Oncol., 41: 36-40, 1991.[Medline]
  13. Sasaki H., Fukushima M. Prostaglandins in the treatment of cancer. AntiCancer Drugs, 5: 131-138, 1994.[Medline]
  14. Fukushima S., Takeuchi Y., Nakano M., Kita T., Kikuchi Y., Fukushima M. {Delta}7-PGA1 lipid microspheres–pharmaceutical properties and preclinical evaluations Yasugi T.et al eds. . Advances in Polyunsaturated Fatty Acid Research, : Elsevier Science Publishers Amsterdam 1993.
  15. Fukushima S., Takeuchi Y., Uetsuki K., Matsushita K., Suzuki M., Furuta K., Kiho T., Noyori R., Kurozumi S., Fukushima M. In vitro antitumor activity and stability in serum of various {Delta}7-PGA1 analogues. Proc. Am. Assoc. Cancer Res., 37: 396 1996.
  16. Fukushima S., Takeuchi Y., Uetsuki K., Kizaki H., Kurozumi S., Fukushima M. In vivo antitumor effect of methylester of 13,14-dihydro-15-deoxy-{Delta}7-PGA1 (TEI-9826) integrated in lipid microsphere. Proc. Am. Assoc. Cancer Res., 37: 395 1996.
  17. Suzuki M., Kiho T., Tomokiyo K., Furuta K., Fukushima S., Takeuchi Y., Nakanishi M., Noyori R. Rational design of antitumor prostaglandins with high biological stability. J. Med. Chem., 41: 3084-3090, 1998.[Medline]
  18. Fukushima S., Takeuchi Y., Yamashita S., Kurozumi S., Fukushima M. Pharmacokinetics in vivo, antitumor activity against 38 human tumor strains in vitro, cell killing kinetics in vitro, and comparison of antitumor effect in vitro of {Delta}7-PGA1 analogues. Proc. Am. Assoc. Cancer Res., 39: 315 1998.
  19. Fukushima S., Takeuchi Y., Kurozumi S., Suzuki M., Furuta K., Noyori R., Kiho T., Fukushima M. Antitumor activity of {Delta}7-PGA1, its analogs and {Delta}12-PGJ2 in vitro and in vivo. Prostaglandins Leukotorienes Essent. Fatty Acids, 55 (Suppl. 1): 112 1996.
  20. Fukushima S., Takeuchi Y., Kurozumi S., Fukushima M. In vivo antitumor activity of 13,14-dihydro 15-deoxy-{Delta}7-PGA1 methylester (TEI-9826) integrated in lipid microsphere at various administration routes. Prostaglandins Leukotrienes Essent. Fatty Acids, 55 (Suppl. 1): 112 1996.
  21. Kobori O., Vuilloyt M. T., Martin F. Growth responses of rat stomach cancer cells to gastro-pancreatic hormones. Int. J. Cancer, 30: 65-67, 1982.[Medline]
  22. McClay E. F., Winski P. J., Jones J. A., Tennerette J., III, Gattoni-Celli S. {Delta}12-Prostaglandin-J2 is cytotoxic in human malignancies and synergises with both cisplatin and radiation. Cancer Res., 56: 3866-3869, 1996.[Abstract/Free Full Text]
  23. McClay E. F., Jones J. A., Wang L. M., Gattoni-Celli S. {Delta}12PGJ2/cisplatin (DDP) synergy in human melanoma cells (T-289) is mediated via an apoptotic mechanism. Proc. Am. Assoc. Cancer Res., 39: 157 1998.
  24. Kanazawa M., Yoshida T., Onde M., Andoh Y., Tsuchiya A., Abe R. Growth inhibition and cell cycle progression of {Delta}12-PGJ2 on human colon cancer cell lines. J. Jpn. Cancer Ther., 32: 221-229, (in Japanese, English abstract) 1997.
  25. Louie K. G., Behrens B. C., Kinsella T. J., Hamilton T. C., Grotzinger K. R., McKoy W. M., Winker M. A., Ozols R. F. Radiation survival parameters of antineoplastic drug-sensitive and -resistant human ovarian cancer cell lines and their modification by buthionine sulfoximine. Cancer Res., 45: 2110-2115, 1985.[Abstract/Free Full Text]
  26. Akimaru K., Kuo M. T., Furuta K., Suzuki M., Noyori R., Ishikawa T. Induction of MRP/GS-X pump and cellular resistance to anticancer prostaglandins. Cytotechnology, 19: 221-227, 1996.[Medline]
  27. Ishikawa T., Akimaru K., Ruo M. T., Nakanishi M., Tomokiyo R., Furuta K., Suzuki M., Noyori R. Anticancer prostaglandin-induced cell cycle arrest and its modulation by a specific inhibitor of MRP/GS-X pump. Proc. Am. Assoc. Cancer Res., 38: 590 1997.



This article has been cited by other articles:


Home page
 Cell Growth Differ.Home page
P. A. Campo, S. Das, C.-H. Hsiang, T. Bui, C. E. Samuel, and D. S. Straus
Translational Regulation of Cyclin D1 by 15-Deoxy-{Delta}12,14-Prostaglandin J2
Cell Growth Differ., September 1, 2002; 13(9): 409 - 420.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Hayes, B. R. Lane, S. R. King, D. M. Markovitz, and M. J. Coffey
Peroxisome Proliferator-activated Receptor gamma Agonists Inhibit HIV-1 Replication in Macrophages by Transcriptional and Post-transcriptional Effects
J. Biol. Chem., May 3, 2002; 277(19): 16913 - 16919.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sasaki, H.
Right arrow Articles by Fukushima, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sasaki, H.
Right arrow Articles by Fukushima, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online