Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: Diminution of tumorigenicity with a corresponding decrease in the production of prostaglandin E2

Summary To determine whether resistance to chemoimmunotherapy is acquired during therapy, we investigated the effects of chemotherapeutic agents and anti-tumour polysaccharide, lentinan, on the progression of Rous sarcoma virus-induced S908.D2 fibrosarcomas. The chemoimmunotherapy was effective against the parental S908.D2-bearing mice. Nearly all the mice that were treated with cyclophosphamide (CY) and lentinan achieved complete tumour regression. Only a few of the mice that achieved complete regression of the primary tumours showed a recurrence of the tumour in regional lymph nodes. S908.D2-vp.1 was established from metastatic tumours that developed in the regional lymph nodes of parental S908.D2-bearing mice during therapy. S908.D2-vp.2-or vp.3 cells were sequentially derived in a similar way from S908.D2-vp. 1-or-vp.2-bearing mice respectively, im which complete tumour regression at each primary site was achieved during therapy. These lines acquired resistance to CY and lentinan and also to 5-fluorouracil (5-FU)/5'-deoxy-5-fluorouracil and lentanin. No significant difference in either the sensitivity to 5-FU or 4-deoxycyclophosphamide in vitro or in the susceptibility to immune effector cells was observed between the parental and progressed lines (S908.D2-vp.1--vp.3). There was an increase in the level of prostaglandin E2 (PGE2) in the progressed lines during repeated therapy (parental, 1171 pg ml-1; vp.1, 2199 pg ml-'; vp.2, 5500 pg m 1-1; vp3, 16187 pg ml-'). There was no significant increase in the production of transforming growth factor ,B (TGF-,B). The amount of interleukin-2 (IL-2) produced by spleen cells isolated from the S908.D2-vp.2-bearing mice was decreased compared with the amount produced by the parental S908.D2-bearing mice. Furthermore, combination therapy with lentinan and IL-2 achieved complete tumour regression in all the mice transplanted with S908.D2 progressed tumour lines, although IL-2 alone did not show any anti-tumour effects in either the S908.D2 parental or progressed lines. The findings suggest that the reduced production of IL-2 induced an increase in the production of the PGE2 by progressed tumour lines is involved in the acquisition of resistance.

Section: Disussionmentioning

confidence: 99%

Cancer cell progression and chemoimmunotherapy-dual effects in the induction of resistance to therapy

Hamuro

Kikuchi²,

Takatsuki³

et al. 1996

“…The mice were maintained in the specific pathogen-free animal facility at the Institute for Animal Experiments, Hokkaido University School of Medicine. Tumour BMT-1 1 tumour is a transplantable fibrosarcoma induced by 3-methylcholanthrene in a C57BL/6 mouse (Ishikawa et al, 1987;Okada et al, 1990). The tumour cells were maintained as a monolayer culture in Eagle's minimum essential medium (EMEM) with 10% heat-inactivated fetal bovine serum (FBS).…”

mentioning

confidence: 99%

Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant

Kuramitsu

Nishibe²,

Kobayashi³

et al. 1996

Summary Using an under agarose migration (UAM) assay, we studied lymphokine-activated killer (LAK)-attractant activity in cultured conditioned medium of tumour tissues after chemotherapy as a possible mechanism of enhanced LAK cell accumulation into tumour tissues after chemotherapy. BMT-11 is a fibrosarcoma developed in C57BL/6 mice. The conditioned medium of BMT-11 tumour tissues obtained from mice treated with various anti-cancer drugs had chemotactic activity for LAK cells (LAK-attractant activity). mRNA expression of interleukin (IL)-la, IL-6, IL-8, interferon (IFN)-y, and tumour necrosis factor (TNF)-a was observed in untreated tumour tissues, which were not enhanced by cyclophosphamide treatment. mRNA expression of TGF-,IB was not detected in untreated tumour tissues by reverse transcription-polymerase chain reaction (RT-PCR), but was detected in tumour tissues treated with cyclophosphamide. Recombinant human TGF-,B1 showed LAK-attractant activity at a concentration of 0.1 ng ml-1 and 1 ng ml-', whereas fresh splenocytes were not attracted by TGF-f,1. Anti-TGF-,B1 antibody inhibited LAK-attractant activity in the conditioned medium of tumour tissues treated with cyclophosphamide to approximately 35% that of control at 100 Mg ml -l. These findings indicate that TGF-,13 produced in the tumour tissues of mice treated with anticancer drugs could be a LAK attractant. By a 4 h 51 Cr release assay of natural killer cell-resistant BMT-11 tumour cells, we observed that TGF-,B1 at a concentration from 0.01 ng ml-1 to 10 ng ml-1 did not inhibit LAK activity in an effector phase. Taken together, we suggest that TGF-,B1 produced in tumour tissues after chemotherapy participates in gathering transferred LAK cells and contributes to the therapeutic effects of transferred LAK cells.

“…Tumour-derived PGE2 promotes the in vivo growth of tumour cells by suppressing the host anti-tumour immune defences (Catalona & Chretien, 1973;Jessup et al, 1976;Anderson et al, 1981). When prostaglandin levels in tumourbearing mice are reduced by the oral administration of an inhibitor of PGE2 synthesis, indomethacin, or by use of antibodies against PGE2, immunosuppression is also reduced and tumour development is significantly diminished (Lynch & Salomon, 1979;Young & Dizer, 1983;Young & Knies, 1984;Okada et al, 1990). These studies reveal an evident parallelism between the level of PGE2 production and the growth and malignant progression of tumour cells (Rolland et al, 1990).…”

mentioning

confidence: 99%

“…We have previously reported that a clone (QR-32 cells) derived from a cultured mouse fibrosarcoma, BMT-l1 cl-9, spontaneously regresses in normal syngeneic C57BL/6 mice (Ishikawa et al, 1987a, Okada et al, 1990. We considered that, because PGE2 suppressed the anti-tumour effector cell induction at the site of tumour implantation in the tumorgenic parental BMT-11 cl-9 cells, the regression of QR-32 cells was likely to be due to a decrease in the production of PGE2 (Okada et al, 1990)_ We have also observed that oxygen radicals produced by host cells reactive to foreign bodies such as gelatin sponge augment the production of PGE2 by QR-32 cells during co-culture in vitro.…”

mentioning

confidence: 99%

“…We considered that, because PGE2 suppressed the anti-tumour effector cell induction at the site of tumour implantation in the tumorgenic parental BMT-11 cl-9 cells, the regression of QR-32 cells was likely to be due to a decrease in the production of PGE2 (Okada et al, 1990)_ We have also observed that oxygen radicals produced by host cells reactive to foreign bodies such as gelatin sponge augment the production of PGE2 by QR-32 cells during co-culture in vitro. The enhanced production of immunosuppressive PGE2 facilitates the progressive growth of tumours in normal mice when they are given a subcutaneous injection of mixtures of host cells reactive to gelatin sponge and QR-32 cells (Okada et al, 1992).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Enhancement of in vitro prostaglandin E2 production by mouse fibrosarcoma cells after co-culture with various anti-tumour effector cells

Okada

Hosokawa²,

Hasegawa³

et al. 1994