Cancer cell progression and chemoimmunotherapy--dual effects in the induction of resistance to therapy.
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, in 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 lentinan. 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-vp1 -vp3). 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(-1); vp.2, 5500pg ml(-1); vp3, 16187 pg ml(-1)). There was no significant increase in the production of transforming growth factor beta (TGF-beta). 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.
Hamuro
J
J
Basic Research Laboratories, Central Research Laboratories, Ajinomoto Co., Kawasaki, Japan.
Kikuchi
T
T
Takatsuki
F
F
Suzuki
M
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001358:Avian Sarcoma Viruses; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D015232:Dinoprostone / Q000096:biosynthesis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005472:Fluorouracil / Q000627:therapeutic use*; D007167:Immunotherapy; D007376:Interleukin-2 / Q000096:biosynthesis; D007912:Lentinan / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D007912:Lentinan; D003520:Cyclophosphamide; D015232:Dinoprostone; D005472:Fluorouracil