The introduction of the “maximum tolerated dose” in usual treatment protocols (and its concomitant overt toxicity) made necessary the imposition of rest periods between cycles of therapy—a practice that not only involves re-growth of tumour cells, but also growth of selected clones resistant to the therapy. To avoid the problems caused by traditional chemotherapeutic regimens, a new modality of drug administration called “metronomic chemotherapy” has been proposed. This name makes reference to the chronic, equally spaced administration of (generally) low doses of various chemotherapeutic drugs without extended rest periods. The novelty of this treatment modality lies not only in its antitumour efficacy with very low toxicity, but also in a cell target switch, now aiming at tumour endothelial cells. The knowledge acquired in the experimental field of metronomic chemotherapy, plus the increasing experience that is being obtained in the clinical setting, will help to lead a change in the design of therapeutic protocols against cancer.

Background: Preclinical results showing therapeutic effect and low toxicity of metronomic

Metronomic chemotherapy (MCT),

Metronomic chemotherapy (MCT) is a novel therapeutic strategy for cancer treatment endowed with an antiangiogenic effect. It refers to regular administration of low doses of cytotoxic drugs, with minimal or no drug-free breaks. Previously, we demonstrated the immunomodulating activity of a single low-dose of cyclophosphamide (Cy) and the antitumor effect of MCT with Cy on established rat lymphomas and sarcomas. Here, we examined whether the immune response is responsible for the antitumor effect of MCT with Cy on L-TACB lymphoma. Inbred e rats and nude mice were subcutaneously challenged with L-TACB. After 7 days, they were distributed into two experimental groups: 1) treated animals, which were injected IP with Cy (10 mg/kg body weight) three times per week, and 2) control animals, which received IP saline injections. Exponential growth and decay and tumor doubling time were calculated. Also, serum IL-10 levels were measured. One hundred percent of treated rats showed tumor regression versus 0% of control rats. The increase of tumor-induced IL-10 levels was reverted by the treatment with Cy. On the other hand, there were no tumor regressions, in treated or control nude mice. However, the tumor doubling times of treated nude mice were significantly higher than those of control mice, implying that other antitumor mechanism(s), independent of the adaptive immune response, might be taking place. Our present results indicate that modulation of the immune response would be involved in the antitumor effect of MCT with Cy, because the absence of the specific immune response impairs, at least in part, its therapeutic effect in a lymphoma tumor model.Key words: Metronomic chemotherapy; Immune response; Lymphoma; Cyclophosphamide INTRODUCTIONapy (100% and 83% complete tumor regression, respectively), that does not cause loss of weight and is devoid of hematological, cardiac, hepatic, and renal toxicity (7). Metronomic chemotherapy (MCT) is a novel therapeutic strategy for cancer treatment. It refers to regular Preclinical and clinical experiments have shown that the therapeutic effect of MCT is achieved through inhibition administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over proof angiogenesis (1,8,9). Our objective here was to investigate whether the immune response is also responsible longed periods of time (1). We have previously demonstrated that a single low dose of cyclophosphamide (Cy), for the antitumor effect obtained with metronomic administration of Cy in a rat lymphoma model. a treatment completely devoid of toxicity, inhibits the growth of spontaneous and experimental metastasis of a rat lymphoma, while it does not affect primary tumor MATERIALS AND METHODS growth (2). Such an effect would be mainly due to modAnimals ulation of the immune response (3-6). We also demonstrated that administration of Cy at low doses on a thrice Inbred adult female IIM e/Fm rats (10) from the Facultad de Ciencias Médicas, Universidad Nacional de weekly schedule, with no rest perio...

The therapeutic benefits of combined MCT with cyclophosphamide plus celecoxib on mammary adenocarcinomas together with its very low toxicity profile warrant further study in an attempt to make the translation into the clinic.

No abstract

Loss of BRCA2 function stimulates prostate cancer (PCa) cell invasion and is associated with more aggressive and metastatic tumors in PCa patients. Concurrently, the receptor tyrosine kinase c-kit is highly expressed in skeletal metastases of PCa patients and induced in PCa cells placed into the bone microenvironment in experimental models. However, the precise requirement of c-kit for intraosseous growth of PCa and its relation to BRCA2 expression remain unexplored. Here, we show that c-kit expression promotes migration and invasion of PCa cells. Alongside, we found that c-kit expression in PCa cells parallels BRCA2 downregulation. Gene rescue experiments with human BRCA2 transgene in c-kit-transfected PCa cells resulted in reduction of c-kit protein expression and migration and invasion, suggesting a functional significance of BRCA2 downregulation by c-kit. The inverse association between c-kit and BRCA2 gene expressions in PCa cells was confirmed using laser capture microdissection in experimental intraosseous tumors and bone metastases of PCa patients. Inhibition of bone-induced c-kit expression in PCa cells transduced with lentiviral short hairpin RNA reduced intraosseous tumor incidence and growth. Overall, our results provide evidence of a novel pathway that links bone-induced c-kit expression in PCa cells to BRCA2 downregulation and supports bone metastasis.

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