Para ello se utilizaron ratones que portaban diferentes tumores (NSCLC, gástrico, de páncreas o colon) obtenidos de pacientes, y que recibieron tratamiento con PM060184.A continuación se determinó el efecto antitumoral del tratamiento y así, se demostró una reducción del tamaño tumoral muy importante alcanzándose, en algunos casos (NSCLC o gástrico) la desaparición completa del tumor implantado.
**********************************************
Background:
PM060184 is a synthetic marine-derived compound originally isolated from the marine sponge Lithoplocamia lithistoides. PM060184 induces disorganization and disruption of the microtubule network as well as aberrant mitotic spindle multipolarization and chromosome missegregation. These effects give rise to prometaphase arrest and formation of multinucleated cells. Then, cells enter to caspase-driven apoptosis or are arrested in a pseudo-senescent state. PM060184 is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases.
Material and Methods:
Athymic female nu/nu mice were subcutaneously implanted with different patient-derived tumors: NSCLC (N=4)), pancreas (N=5), colon (N=4) and gastric (N=2). Tumor (ca. 300 mm3) bearing animals (N=6-10/group) were randomly allocated to receive PM060184 (16 mg/kg) or placebo. Treatments were administered weekly for 5 consecutive weeks. Antitumor effect was calculated using ΔT/ΔC (%), defined as a percentage of the change in tumor size for treated (T) and placebo (C) groups during the placebo-treated survival time (D). Complete tumor regression (CR) was defined when tumor volume < 63 mm3 for 2 or more consecutive measurements.
Results:
The treatment with PM060184 produced lowest ΔT/ΔC values summarized as follows:
Tumor Minimal ΔT/ΔC (%) on Day :
NSCLC Pulm-005 2.2 32
Pulm 009 20.4 14
Pulm-016 0.0 45
Pulm-021 14.7 38
Pancreas Panc-215 37.3 35
Panc-265 12.1 26
Panc-354 29.5 32
JH-024 50.0 39
Colon CCR-020 51.6 28
CCR-025 35.6 39
CCR-029 33.5 35
CCR-030 34.3 28
Gastric Gastric-008 53.3 31
Gastric-010 2.5 38
During the treatment, complete remissions (CR) of tumors were also seen in animals bearing the following xenografts: Pulm-005 (7 CR/7 mice), Pulm-016 (10 CR/10 mice) and Gastric-010 (9 CR/9 mice).
Conclusion:
The treatment with PM060184 demonstrated significant in vivo antitumor activity in patient-derived xenografts of human NSCLC, pancreas, colon and gastric tumors.