ABSTRACT
Metronomic chemotherapy refers to the chronic, equally spaced, delivery of low doses of chemotherapeutic drugs, without extended interruptions. Previously, we developed two combined metronomic schemes for the treatment of murine mammary tumors. The aim of this study was to compare their effects on tumor and metastasis growth, survival, and toxicity. Metronomic chemotherapy with Cyclophosphamide + Celecoxib (Cy + Cel) showed higher antimetastatic power than Cyclophosphamide + Doxorubicin (Cy + Dox), while being similar in other aspects. That difference, plus the advantage that represents its oral administration, suggests that the Cy + Cel combination is more suitable than Cy + Dox for metronomic chemotherapy of mammary tumors and could be proposed to the translation to the clinic.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Drug Evaluation, Preclinical , Analysis of Variance , Animals , Drug Administration Schedule , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/mortality , Mammary Neoplasms, Experimental/pathology , Mice , Neoplasm Metastasis , Tumor Burden/drug effectsABSTRACT
BACKGROUND: Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended rest periods. Herein, we investigated the therapeutic efficacy of metronomic cyclophosphamide (Cy) combined with doxorubicin (Dox) in two mouse mammary adenocarcinoma models. MATERIALS AND METHODS: Mice were s.c. challenged with M-234p or M-406 mammary tumors, and when the tumors reached â¼150 mm(3), they were treated with: (I) no treatment (controls); (II) Cy in the drinking water (30 mg/kg body weight/day); (III) Dox (0.5 mg/kg body weight i.p. three times/week); (IV) treated as (II) + (III). Mice challenged i.v. with M-234p or M-406 tumor cells received, on day 3, the same treatments. RESULTS: We found that MCT with Cy plus Dox inhibited tumor growth, decreased lung metastases, and increased the median survival time, while having low toxic effect. Combined MCT was more effective than each monotherapy causing decrease in VEGF serum concentration and tumor proliferation rate plus increase in tumor apoptosis. CONCLUSION(S): The therapeutic benefits of combined MCT with Cy and Dox on mammary adenocarcinomas together with its low toxic effect profile suggest the possibility of future translation into the clinic.
Subject(s)
Adenocarcinoma/drug therapy , Administration, Metronomic , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Mammary Neoplasms, Animal/drug therapy , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/therapeutic use , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Cyclophosphamide/therapeutic use , Disease Models, Animal , Doxorubicin/therapeutic use , Female , Ki-67 Antigen/metabolism , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Mice , Mice, Inbred BALB C , Neoplasm Metastasis/prevention & control , Neovascularization, Pathologic/drug therapy , Survival , Vascular Endothelial Growth Factor A/bloodABSTRACT
AIM: Experimental and clinical studies showed that the administration of cyclophosphamide (Cy) in low doses leads to an enhancement of the antitumor immune response. Our objective was to study the modulation, if any, by low dose Cy, of T regulatory (Treg) and natural killer T (NKT) I cells, two cell populations of the innate immune response with opposing effects on the tumors, in a rat B cell lymphoma model. METHODS: Inbred e rats were challenged s.c. with L-TACB lymphoma and on day 14 animals were distributed in two groups. Treated: injected i.p. with cyclophosphamide (10mg/kg of body weight) and CONTROL: injected i.p. with saline. Blood samples were taken from days 0 to 21 and the percentage of T regulatory and natural killer T I cells were determined by flow cytometry. RESULTS: We found that the increase of natural and inducible T regulatory cells of peripheral blood achieved during tumor growth was significantly downregulated by cyclophosphamide. On the contrary, natural killer T I cells were not modulated by the treatment. CONCLUSION: The antimetastatic effect of a single low dose of Cy would be due, at least in part, to downregulation of natural and inducible T regulatory cells.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Cyclophosphamide/administration & dosage , Lymphoma, B-Cell/immunology , Natural Killer T-Cells/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Animals , Disease Models, Animal , Female , Lymphoma, B-Cell/drug therapy , RatsABSTRACT
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.
