ABSTRACT
The vasopressin peptide analog desmopressin has been used during surgery to prevent bleeding in patients with coagulation defects. Recent experimental and clinical data revealed that perioperative desmopressin therapy can minimize the spread and survival of residual cancer cells. Here, we explored the antitumor effects of desmopressin in combination with chemotherapeutic agents using the F3II mammary carcinoma in syngeneic Balb/c mice. Intravenous administration of desmopressin at a dose of 2 microg/kg together with weekly cycles of carmustine (20 mg/kg) prevented primary tumor infiltration of the skin. Combination of desmopressin with paclitaxel (25 mg/kg) significantly reduced metastatic progression to the lung. Although desmopressin had an antiproliferative effect on F3II cells, in vitro studies did not demonstrate an enhanced cytotoxicity with chemotherapy. Our results suggest that desmopressin may contribute to impair aggressiveness of residual mammary tumors during chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Deamino Arginine Vasopressin/pharmacology , Mammary Neoplasms, Experimental/drug therapy , Animals , Carmustine/administration & dosage , Carmustine/pharmacology , Cell Growth Processes/drug effects , Deamino Arginine Vasopressin/administration & dosage , Drug Synergism , Female , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB CABSTRACT
We designed high-affinity primers for the mRNA sequence of human tyrosinase to test the value of molecular detection of circulating melanoma cells by reverse transcription-polymerase chain reaction (RT-PCR). The optimization process included in vitro settings and in vivo studies in a xenograft mouse model. We detected tyrosinase expression with at least 40 pg and 1.5 pg of total RNA extracted from cultured SKmel human melanoma cells, using a first round of PCR amplification and nested PCR, respectively. Human tyrosinase expression was found in the blood of nude mice bearing subcutaneous SKmel tumors, and the expression bands were stronger after manipulation of the tumor mass. We also examined the fate of circulating melanoma cells in the present melanoma model. Tyrosinase expression declined in blood 6 h after a direct intravenous injection of SKmel cells. A preliminary study in human blood samples demonstrated a baseline positive tyrosinase determination in 64% (16/25) of advanced melanoma patients using the RT-PCR nested assay. Baseline tyrosinase expression was significantly associated with disease progression after 12 months, and sequential determination during follow-up of the remaining disease-free patients showed a progressive increase of negative results.
Subject(s)
Melanoma/blood , Melanoma/enzymology , Monophenol Monooxygenase/genetics , RNA, Messenger/blood , Transplantation, Heterologous , Animals , Cell Line, Tumor , Disease Models, Animal , Humans , Melanoma/diagnosis , Melanoma/pathology , Mice , Mice, Nude , PrognosisABSTRACT
Desmopressin (DDAVP) is a well tolerated and convenient haemostatic agent that can be used in a number of clinical conditions with bleeding diathesis. It has several effects on the haemostatic system, causing endogenous release of coagulation factor VIII, von Willebrand factor and tissue-type plasminogen activator, among others. In this review we present a growing body of evidence showing that DDAVP treatment may impair spread of cancer cells and contribute to encapsulation of tumour tissue. Our data in preclinical animal models suggest a potential application of DDAVP in the perioperative management of aggressive solid tumours. Novel vasopressin analogues with improved antitumor effects are currently in development.
Subject(s)
Deamino Arginine Vasopressin/therapeutic use , Hemostatics/therapeutic use , Neoplasms/drug therapy , Animals , Humans , Neoplasm Invasiveness , Neoplasms/pathology , Vasopressins/therapeutic useABSTRACT
BACKGROUND AND OBJECTIVES: Desmopressin (DDAVP) is a synthetic derivative of vasopressin with hemostatic and fibrinolytic properties that has been used during surgery in patients with bleeding disorders. Our aim was to investigate the effect of DDAVP on lung and lymph node metastatic cell colonization using a preclinical mouse mammary carcinoma model of subcutaneous tumor manipulation and surgical excision. METHODS: Female BALB/c mice bearing the highly aggressive F3II mammary carcinoma were subjected to repeated manipulations of primary tumors (0.5 kg/cm(2) during 2 min), followed (or not) by surgical excision. DDAVP was administered intravenously 30 min before and 24 h after each manipulation or surgery, at a dose of 2 microg/kg. At the end of the experiment, mice were sacrificed and necropsied. RESULTS: Tumor manipulation induced dissemination to the axillary nodes and increased up to 6-fold the number of metastatic lung nodules. Perioperative treatment with DDAVP dramatically reduced regional metastasis. The incidence of lymph node involvement in manipulated animals was 12% with DDAVP and 87% without treatment (P < 0.02). Histopathological analysis of axillary nodes from DDAVP-treated animals showed sinusal histiocytosis and no evidence of cancer cells. Metastatic lung nodules were also reduced about 65% in animals treated with DDAVP (P = 0.026). CONCLUSIONS: Our results suggest a potential clinical application of DDAVP in the management of breast cancer, as well as other aggressive solid tumors. DDAVP may be useful to reduce the risk of metastatic cell colonization both during and after surgical manipulation.
