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

Ryoyama, Kazuo; Ryoyama, Chizuko

doi:10.1007/bf01742304

Cited by 4 publications

(8 citation statements)

References 26 publications

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“…Our previous study [22] indicates that although Arg(Me) inhibits activity of antitumor macrophages, it does not totally inhibit it when the Arg(Me) dose is increased from 1 mM to 5 raM. This suggests that effector molecules other than L-arginine-dependent nitric oxide are involved in the activity of antitumor macrophages.…”

Section: Other Soluble Effector Moleculesmentioning

confidence: 90%

“…Peritoneal exudate cells (PEC) were obtained from mice pretreated with OK-432, with and without mitomycin-C-treated EL4 (EL4MMC) and CY, as previously described [22]. The cells were washed and resuspended in RPMI-1640 medium (+ L-arginine) containing 0.5% fetal calf serum.…”

Section: Methodsmentioning

confidence: 99%

“…Since our previous study [22] shows that Arg(Me) inhibits antitumor activity of macrophages from mice pretreated either with EL4MI~c and OK-432, or wdth EL4~IMC, OK-432 and CY, L-arginine-dependent nitric oxide might be one of the antitumor molecules of macrophages. In Figure 2 represents the correlation between antitumor and nitrite production activities of macrophages.…”

Section: Correlation Between Antitumor Activity Of and Nitrite Producmentioning

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: 97%

“…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: Other Soluble Effector Moleculesmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Correlation Between Antitumor Activity Of and Nitrite Producmentioning

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: 97%

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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Inhibition of macrophage nitric oxide production by arachidonate-cascade inhibitors

Ryoyama

Nomura

Nakamura

1993

Cancer Immunol Immunother

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We examined whether inhibitors of the arachidonic acid cascade inhibited nitric oxide (NO) production, as measured by nitrite concentration, either in macrophages or by their cytosolic fractions. Nitrite production by peritoneal macrophages from mice receiving OK-432 treatment was significantly inhibited by phospholipase A2 inhibitors [dexamethasone and 4-bromophenacyl bromide (4-BPB)], lipoxygenase inhibitors [nordihydroguaiaretic acid (NDGA) and ketoconazole] and a glutathione S-transferase (leukotrienes LTA4-LTC4) inhibitor (ethacrynic acid). However, caffeic acid and esculetin, inhibitors of 5- and 12-lipoxygenase respectively, were not inhibitory. On the other hand, indomethacin, a cyclooxygenase inhibitor, slightly inhibited whereas another inhibitor, ibuprofen, did not. Inhibition of the nitrite production by dexamethasone, 4-BPB, NDGA and ethacrynic acid was also demonstrated when the macrophages were restimulated ex vivo with OK-432 or with lipopolysaccharide. The inhibitory activity of dexamethasone, NDGA and ethacrynic acid was significantly reduced by ex vivo restimulation with OK-432, whereas that of 4-BPB was hardly affected. Furthermore, the inhibitory activity of dexamethasone, NDGA and ethacrynic acid was much higher when the macrophages were continuously exposed to the agents than when they were pulsed. Meanwhile, inhibition by 4-BPB was almost the same with either treatment. In addition, the inhibitory activity of these agents was not blocked with L-arginine, a substrate of NO synthases, or with arachidonate metabolites (LTB4, LTC4 and LTE4). Ethacrynic acid and 4-BPB, but not dexamethasone and NDGA, also inhibited nitrite production by the cytosolic fractions from OK-432-restimulated peritoneal macrophages, and the inhibitory activity of 4-BPB was superior to that of ethacrynic acid. These agents, however, did not inhibit nitrite production from sodium nitroprusside, a spontaneous NO-releasing compound. These results indicate that dexamethasone, 4-BPB, NDGA and ethacrynic acid inhibited the production of NO by macrophages through at least two different mechanisms: one was inhibited by dexamethasone, NDGA and ethacrynic acid and the other by 4-BPB. Furthermore, 4-BPB and ethacrynic acid directly inhibited the activity of the NO synthase in macrophages, suggesting that the agents work by binding to the active site(s) of the enzyme.

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Immunosuppressive Drug Therapy of Systemic Lupus Erythematosus

Fox

McCune

1994

Rheumatic Disease Clinics of North America

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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

Cited by 4 publications

References 26 publications

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

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

Inhibition of macrophage nitric oxide production by arachidonate-cascade inhibitors

Immunosuppressive Drug Therapy of Systemic Lupus Erythematosus

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