Augmented induction of antitumor cells in vivo by cyclophosphamide fails to benefit antitumor resistance of the host

Ryoyama, Kazuo; Ryoyama, Chizuko

doi:10.1007/bf00199213

Cited by 2 publications

(9 citation statements)

References 16 publications

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“…This study shows that L-arginine-dependent nitric oxide was a major media-tor of antitumor activity of macrophages induced with OK-432 and CY. This supports our previous study [21] that increased and persistent induction by CY treatment of antitumor macrophages is not beneficial to antitumor resistance by the host. Meanwhile, Stuehr and Marletta [25,26] have reported that lipopolysaccharide or bacillus CalmetteGurrin treatment dramatically increases nitrate levels in blood and urine of treated mice and that macrophages are responsible for this nitrate biosynthesis in vivo.…”

Section: Discussionsupporting

confidence: 92%

“…EL4 tumor cells were maintained in vivo and in vitro as previously described [21]. L929 cells were maintained by culturing in Eagle minimum essential medium (Nissui Seiyaku Co., Tokyo) with 10% fetal calf serum and 2 mM L-glutamine.…”

Section: Methodsmentioning

confidence: 99%

“…Antitumor activities of macrophages were determined as previously described [21]. Macrophages were suspended with EL4 cells (104 cells/well), with and without agents, to a total volume of 0.2 ml and incubated in 96-well microplates at 37°C in a humidified CO2 (5%) atmosphere.…”

Section: Methodsmentioning

confidence: 99%

“…However, the addition of CY dose not increase antitumor resistance by the host, although it increases production of antitumor macrophages in vivo [21,22].…”

Section: Introductionmentioning

confidence: 98%

“…We [21,22] have reported that treatment with a nonspecific immunostimulator (OK-432) and mitomycin-Ctreated EL4 cells (EL4MMC) induces antitumor macrophages, and that cyclophosphamide (CY), a chemotherapeutic agent, modifies the induction kinetics of such macrophages. Since antitumor activity of macrophages is inhibited by NG-Monomethyl-L-arginine, nitric oxide appears to affect antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

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Effector molecules from antitumor macrophages induced with OK-432 and cyclophosphamide

Ryoyama

1992

Cancer Immunol Immunother

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The present study was designed to determine whether antitumor activity of macrophages induced with OK-432 and cyclophosphamide was mainly dependent on their ability to produce a soluble factor, that is, L-arginine-dependent nitric oxide as measured by nitrite concentration. Nitrite production by peritoneal macrophages from NIH Swiss mice pretreated with OK-432 (125 KE/kg) i.p. twice at 1-week intervals and with cyclophosphamide (200 mg/kg) i.p. 2 days before the second OK-432 treatment, increased with time for 24 h, and proportionally depended on macrophage numbers. Nitrite production was inhibited by actinomycin D and puromycin but not by mitomycin C. NG-Monomethyl-L-arginine, a specific competitive inhibitor of L-arginine-dependent nitric oxide synthesis, also inhibited production. There was a close correlation between nitrite production and antitumor activity in macrophages from mice pretreated with either OK-432 and cyclophosphamide, OK-432, or thioglycolate broth. OK-432 increased both nitrite production and antitumor activities when added to the macrophage from mice pretreated with OK-432 but not with thioglycolate broth. Both activities of macrophages from mice pretreated with OK-432 and cyclophosphamide were enhanced with increasing concentrations of L-arginine (0.125-1 mM) in the culture medium. D-Arginine, however, did not substitute for L-arginine. Neither activity was affected by contact between the macrophage and the EL4 cell. The macrophage showed antitumor activity through a membrane filter though the activity was greatly reduced. This antitumor activity of macrophages through a membrane was also inhibited by NG-Monomethyl-L-arginine, and increased by OK-432. However, conditioned media, obtained by culturing macrophages induced with OK-432 and cyclophosphamide, inhibited growth of EL4 cells. This activity was carried out by dialysable and non-dialysable factors. One of the dialysable factors was nitrite, an oxidized product of nitric oxide. The antitumor activity of non-dialysable factors was heat-stable and production of factors was increased by NG-Monomethyl-L-arginine and OK-432. Also, non-dialysable factors increased both antitumor and nitrite production activities of OK-432-elicited macrophages, when incubated with factors. Such activity of factors was also heat-stable. The production of factors increased with incubation time of macrophages, and was not inhibited by NG-Monomethyl-L-arginine. These results indicate that in vitro antitumor activity of macrophages induced with OK-432 and cyclophosphamide was mainly dependent on L-arginine-dependent nitric oxide, and that macrophage-associated soluble factors other than nitric oxide were also needed to inhibit fully tumor growth in vitro.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…However, the addition of CY dose not increase antitumor resistance by the host, although it increases production of antitumor macrophages in vivo [21,22].…”

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Effector molecules from antitumor macrophages induced with OK-432 and cyclophosphamide

Ryoyama

1992

Cancer Immunol Immunother

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Cyclophosphamide modifies the induction kinetics but not cell types and cytotoxic mechanisms of antitumor cells elicited with OK-432 plus attenuated tumor cells

Ryoyama

1991

Cancer Immunol Immunother

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The present study was designed to examine whether the antitumor cells induced by treatment with mitomycin-C-treated EL4 cells (EL4MMC) plus OK-432 plus cyclophosphamide differed from those induced by treatment with EL4MMC plus OK-432 in terms of their cell types and antitumor mechanisms. Antitumor activity of peritoneal exudate cells (PEC) from mice receiving either treatment was nonspecific, and inhibition of their target cell growth increased for up to 24 h. Macrophage toxin, silica and trypan blue abrogated the activity in vitro and in vivo, respectively. The activity of the PEC was inhibited with inhibitors of the arachidonic acid cascade, such as dexamethasone, 4-bromophenacyl bromide and nordihydroguaiaretic acid but not esculetin, ibuprofen, indomethacin and BW755C. NG-monomethyl-L-arginine, a specific competitive inhibitor of the L-arginine-dependent nitric oxide synthesis, also inhibited the activity. These results and morphological observations indicated that antitumor cells in the PEC from mice receiving either treatment were macrophages, and that their activity was closely related to the arachidonic acid cascade and to nitric oxide. Antitumor activity of the PEC spontaneously decayed in vitro and this decay was inhibited by the addition of OK-432 or lipopolysaccharide. On the other hand, cyclophosphamide sustained the appearance of antitumor cells in mice treated with EL4MMC plus OK-432. Therefore, cyclophosphamide treatment did not modify cell types and cytotoxic mechanisms of antitumor cells elicited with EL4MMC plus OK-432, but did modify the induction kinetics of such antitumor macrophages.

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Augmented induction of antitumor cells in vivo by cyclophosphamide fails to benefit antitumor resistance of the host

Cited by 2 publications

References 16 publications

Effector molecules from antitumor macrophages induced with OK-432 and cyclophosphamide

Effector molecules from antitumor macrophages induced with OK-432 and cyclophosphamide

Cyclophosphamide modifies the induction kinetics but not cell types and cytotoxic mechanisms of antitumor cells elicited with OK-432 plus attenuated tumor cells

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