Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity.

BACKGROUND: Our aim was to investigate the clinical efficacy and toxicity of metronomic administration of low-dose cyclophosphamide (Cy) in lymphoma and sarcoma rat tumour models. METHODS: Adult inbred rats were challenged with lymphoma TACB and sarcoma E100 s.c. on day 0. Animals were divided into two groups: group I, control, injected with saline three times a week; and group II, treated with Cy 10 mg/kg three times a week, from day 10 until the tumour was non-palpable, or 5 mg/kg three times a week from day 7. Tumours were measured and animals were weighed twice weekly. Periodic blood samples were taken for determination of urea, creatinine, serum glutamic-oxaloacetic transaminase, lactate dehydrogenase and haematological parameters. RESULTS: The administration of low-dose Cy eradicated established rat lymphomas and sarcomas; there was neither metastatic growth nor recurrence at primary sites for 100% of the lymphomas and 83% of the sarcomas. In addition, the treatment did not cause weight loss, and was devoid of haematological, cardiac, hepatic and renal toxicity. CONCLUSIONS: Metronomic administration of Cy at low doses on a thrice weekly schedule to already grown rat lymphomas and sarcomas demonstrated itself to be a successful antitumour therapy that did not cause weight loss and was devoid of haematological, cardiac, hepatic and renal toxicity.

Down regulation of T-cell-derived IL-10 production by low-dose cyclophosphamide treatment in tumor-bearing rats restores in vitro normal lymphoproliferative response.

In previous reports, we demonstrated an inhibitory effect of a single low-dose of cyclophosphamide (Cy) on spontaneous and experimental metastasis of a rat lymphoma (L-TACB). This antimetastatic effect could be adoptively transferred by immune spleen cells from Cy-treated tumor-bearing rats and it was abrogated by the use of immunosuppressed hosts, suggesting an immunomodulatory effect. Subsequently, we found that increased levels of TGF-beta, IL-10 and NO were involved in tumor-induced immunosuppression by inhibiting lymphocyte proliferation. The treatment of tumor-bearing rats with low-dose Cy reduced the splenic production of these suppressive cytokines, restoring the lymphoproliferative capacity otherwise diminished during tumor growth. Here, we investigated the changes of the cytokines modulated by the Cy therapy that are responsible for the restoration of the lymphoproliferative response and determined the spleen cell type producing TGF-beta, IL-10 and NO in our experimental model. Our current results show that IL-10 and NO are produced exclusively by T lymphocytes and macrophages, respectively, whereas TGF-beta is produced by both cell types. The high level of IL-10 produced by T-cells from tumor-bearing rats is responsible for the inhibition of lymphocyte proliferation. Moreover, our results suggest that the shift from immunosuppression to immunopotentiation induced by treatment of tumor-bearing rats with a single low-dose of Cy is mediated by a reduction in T-cell derived IL-10 production, which would account, to some extent, for the antimetastatic effect of Cy treatment.

Inhibition of ras oncogene: a novel approach to antineoplastic therapy.

The most frequently detected oncogene alterations, both in animal and human cancers, are the mutations in the ras oncogene family. These oncogenes are mutated or overexpressed in many human tumors, with a high incidence in tumors of the pancreas, thyroid, colon, lung and certain types of leukemia. Ras is a small guanine nucleotide binding protein that transduces biological information from the cell surface to cytoplasmic components within cells. The signal is transduced to the cell nucleus through second messengers, and it ultimately induces cell division. Oncogenic forms of p21(ras) lead to unregulated, sustained signaling through downstream effectors. The ras family of oncogenes is involved in the development of both primary tumors and metastases making it a good therapeutic target. Several therapeutic approaches to cancer have been developed pointing to reducing the altered gene product or to eliminating its biological function: (1) gene therapy with ribozymes, which are able to break down specific RNA sequences, or with antisense oligonucleotides, (2) immunotherapy through passive or active immunization protocols, and (3) inhibition of p21(ras) farnesylation either by inhibition of farnesyl transferase or synthesis inhibition of farnesyl moieties.