Cancer in mice: effects of prednisolone or mepacrine alone and with cytotoxic drugs

Abstract

Summary WHT/Ht mice were transplanted s.c. with NC carcinoma, and the tumours were excised after 2 weeks. The mice were treated orally throughout the experiments with prednisolone 500pgkg-' or mepacrine 3.6mg kg-1, starting the day after tumour transplantation or, with prednisolone, the day after tumour excision. In some experiments the mice were also treated with the cytotoxic drugs methotrexate 2mg kg 1 and melphalan 1.4mgkg-1. The excised tumours were weighed; some of them, and samples of serum, were extracted for prostanoids which were measured by radioimmunoassay. The chemotherapy lengthened the survival of the mice, but prednisolone or mepacrine had little or no effect on survival, metastasis, the response to chemotherapy, tumour size or the formation of tumour prostanoids.Prostaglandin synthesis inhibitors have been extensively investigated in various murine cancers, and they usually show a beneficial effect (Bennett, 1982;1986). In the NC tumour model the prostaglandin synthesis inhibitors indomethacin or flurbiprofen increase mouse survival and usually reduce tumour size. Survival is even longer when these nonsteroidal anti-inflammatory drugs are used with the cytotoxic drugs methotrexate and melphalan . The effects of the anti-inflammatory drugs seems likely to result from inhibition of prostaglandin synthesis rather than from other properties that the drugs may have (Flower, 1974), since administration of a PGE2 analogue counteracted the effect of indomethacin (Bennett et al., (1985). A similar effect might therefore be expected with other drugs that reduce prostaglandin formation, such as corticosteroids and mepacrine which can inhibit phospholipase activity and so depress the release of prostaglandin precursors (Vane et al., 1982). This action may be particularly relevant to human cancers since prednisolone is frequently used in chemotherapy regimens. We have therefore studied the effects of prednisolone and mepacrine, alone and in combination with the cytotoxic drugs methotrexate and melphalan, in mice with NC tumours. Measurements were made of tumour weight and prostanoid content, the occurrence of metastases, and mouse survival. Materials and methodsThe original NC tumour arose spontaneously in the mammary region of a WHT/Ht mouse (Hewitt et al., 1976) and has since been passaged only in this strain. It has a high incidence of local lymphatic spread, recurrence in the scar following tumour excision, and metastasis mainly to the lungs and mediastinum.On day 0, male or female WHT/Ht mice were injected s.c. into the left flank with -106 NC carcinoma cells in a singlecell suspension from passaged tumours as described previously (Bennett et al., 1979. All tumours were excised at 2 weeks and weighed. The study consisted of 6 separate experiments, each with 9-15 WHT/Ht mice/group. Drugs were given orally in 0.1 ml 50% syrup BP for 5 days (Monday to Friday) each week, and treatment with prednisolone or mepacrine was continued until death or the end of the experiment (day 121). The doses chosen are approx...

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

“…No effect on spontaneous metastases of NC (mammary carcinoma) tumors in mice 145 ; no effect on experimental metastases from C22LR (osteosarcoma) cells in mice 291…”

“…144 In contrast, in WHT/Ht mice injected sc with ~1 × 10 6 NC carcinoma cells (tumors resected on day 14) and treated with prednisone (administered orally at a dose of 0.5 mg/kg for up to 121 days starting on day 0), no effect on local, lymph node or pulmonary metastases was observed. 145…”

“…144 In contrast, in WHT/Ht mice injected sc with *1 Â 10 6 NC carcinoma cells (tumors resected on day 14) and treated with prednisone (administered orally at a dose of 0.5 mg/kg for up to 121 days starting on day 0), no effect on local, lymph node or pulmonary metastases was observed. 145 In summary, testing these drugs gave highly variable results. Depending on the type of tumor, the route of tumor cell inoculation, the immunosuppressive drug, the dose levels administered, and the dosing schedules, increased, decreased, or no effect on tumor growth or incidence of metastases was observed.…”

“…Increased growth (tumor take) of transplanted 3-methylcholanthrene-induced (squamous cell carcinoma) tumors in rats 265 ; no effect on growth of colon 26/clone 20 (colon) tumors in mice 266 ; no effect on tumor growth or survival with MC (mammary carcinoma) in mice 145 ; decreased growth of B16 (melanoma) in mice 138…”

Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine

“…4,6 The development of cell resistance to chemotherapy may be due to the survival and growth of tumor cells originally resistant or to the emergence of mutant cell clones that develop a newly acquired resistance. 24 Because quinacrine lacks antineoplastic properties, 2 it was apparent that the optimization of carmustine treatment for experimental malignant glioma, achieved by the addition of the antimalarial quinacrine, was due to its strong antimutagenic effect. 14,19,23 In a previous experimental study involving cultured C6 glioma cells and C6 rat malignant glioma, we demonstrated that quinacrine, an antimalarial drug with strong antimutagenic properties, administered in adherence to a chronic schedule maintained unchanged, the initial cytotoxic effect of the antineoplastic carmustine, which led to a high rate of tumor resolution in animals and optimal carmustine-induced toxicity in cultured C6 glioma cells.…”