Resumen:
Colorectal cancer (CRC) is a leading cause of cancer-associated
mortality worldwide. Despite being an essential component of systemic
chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe
limitations, such as high toxicity, low selectivity and drug resistance.
[V(4)Q(5)]dDAVP (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) is a
peptide vasopressin analog and a selective agonist of the arginine vasopressin
type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue.
This synthetic compound has well-proven antitumor and antimetastatic activity in
different tumor types, including metastatic CRC. The objective of this work was
to assess the potential combinational benefits in preclinical CRC models after
[V(4)Q(5)]dDAVP addition to 5-FU. METHODS: Effects on cellular viability, cell
cycle progression, apoptosis and molecular mechanisms associated to
[V(4)Q(5)]dDAVP treatment in combination with 5-FU were evaluated in murine CT-26
and human COLO-205 cell lines. In vivo, impact of dual therapy was explored on
CRC tumor growth and metastatic spread. RESULTS: In CRC cells, [V(4)Q(5)]dDAVP (1
µM) addition to sub-IC(50) 5-FU concentrations resulted in the enhancement of
cytostatic effects induced by chemotherapy. Reduction of cell viability after
combined treatment was associated with cell cycle arrest in the G(0)/G(1) phase,
induction of apoptosis and increased gene expression of the cyclin-dependent
kinase inhibitor p21 (CDKN1A) and the tumor suppressor p53 (TP53) in malignant
cells, as assessed by flow cytometry, terminal deoxynucleotidyl
transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL),
and quantitative reverse transcription polymerase chain reaction (qRT-PCR),
respectively. In vivo, intravenous administration of [V(4)Q(5)]dDAVP (0.3 µg/kg)
in combination with safe low doses of 5-FU (50 or 80 mg/kg for CT-26 or COLO-205
tumor models, respectively) effectively abrogated CRC growth, reducing
aggressiveness of primary lesions and increasing survival of tumor-bearing mice.
In addition, concomitant administration of [V(4)Q(5)]dDAVP and 5-FU inhibited
pulmonary metastasis formation by CT-26 cells in immunocompetent mice, especially
reducing macrometastatic disease. CONCLUSIONS: [V(4)Q(5)]dDAVP seems to enhance
the efficacy of 5-FU-based chemotherapy in CRC by modulating tumor progression,
as well as metastatic dissemination, suggesting its potential role as a safe and
cost-effective co-adjuvant agent for the management of advanced CRC.
