Antiangiogenetische Therapie des humanen Pankreaskarzinoms durch einen EGF-Rezeptor-Antikoerper nach orthotoper Implantation in die Nacktmaus
Beschreibung
vor 17 Jahren
Deregulation of epidermal growth factor receptor (EGFR) pathways
contributes to the progression of a wide range of cancers, and the
EGFR is an attractive therapeutic target. The humanized
EGFR-specific monoclonal antibody EMD72000 has shown potent
inhibitory activity in preclinical experiments and is under
investigation in clinical studies. Using the human L3.6pl
pancreatic cancer cell line, we investigated whether the efficacy
of EMD72000 can be enhanced in combination with gemcitabine. Nude
mice were orthotopically injected with L3.6pl cells followed by
biweekly treatment of 40 mg/kg EMD72000 and 100 mg/kg gemcitabine
(either alone or in combination). Under two treatment schedules we
evaluated a) the influence of different time points of initiation
of single agent and combined treatment after tumor cell injection
into nude mice and b) the influence of different treatment
durations. In the first experiment, treatment was initiated at four
different time-points after tumor cell injection (days 8 - 28).
Exposure to EMD72000 or gemcitabine alone resulted in detectable
tumor shrinkage and reduced lymph node and liver metastases,
however, these effects were enhanced in the EMD72000 plus
gemcitabine groups. Furthermore, combination treatment as well as
EMD72000 monotherapy led to a significant reduction of microvessel
density and tumor cell proliferation in primary pancreatic tumors
following immunohistochemical analysis for CD31 and Ki67,
respectively. Overall, the effects were strongest when treatment
was initiated at early time points after tumor cell injection. In a
second experimental set-up, treatment was initiated at day 8 after
tumor cell injection in all cases and stopped at four different
time-points (days 15 - 33). Interestingly, there was no significant
difference in the average tumor weight of the groups treated for
short versus longer time periods. The treatment was most effective
when given shortly after tumor cell injection, whereas the duration
of the treatment appeared less important in this model. In
conclusion, in this model the anti-angiogenic and anti-tumor
activity of EMD72000 in combination with gemcitabine was
substantially more effective than either treatment alone.
contributes to the progression of a wide range of cancers, and the
EGFR is an attractive therapeutic target. The humanized
EGFR-specific monoclonal antibody EMD72000 has shown potent
inhibitory activity in preclinical experiments and is under
investigation in clinical studies. Using the human L3.6pl
pancreatic cancer cell line, we investigated whether the efficacy
of EMD72000 can be enhanced in combination with gemcitabine. Nude
mice were orthotopically injected with L3.6pl cells followed by
biweekly treatment of 40 mg/kg EMD72000 and 100 mg/kg gemcitabine
(either alone or in combination). Under two treatment schedules we
evaluated a) the influence of different time points of initiation
of single agent and combined treatment after tumor cell injection
into nude mice and b) the influence of different treatment
durations. In the first experiment, treatment was initiated at four
different time-points after tumor cell injection (days 8 - 28).
Exposure to EMD72000 or gemcitabine alone resulted in detectable
tumor shrinkage and reduced lymph node and liver metastases,
however, these effects were enhanced in the EMD72000 plus
gemcitabine groups. Furthermore, combination treatment as well as
EMD72000 monotherapy led to a significant reduction of microvessel
density and tumor cell proliferation in primary pancreatic tumors
following immunohistochemical analysis for CD31 and Ki67,
respectively. Overall, the effects were strongest when treatment
was initiated at early time points after tumor cell injection. In a
second experimental set-up, treatment was initiated at day 8 after
tumor cell injection in all cases and stopped at four different
time-points (days 15 - 33). Interestingly, there was no significant
difference in the average tumor weight of the groups treated for
short versus longer time periods. The treatment was most effective
when given shortly after tumor cell injection, whereas the duration
of the treatment appeared less important in this model. In
conclusion, in this model the anti-angiogenic and anti-tumor
activity of EMD72000 in combination with gemcitabine was
substantially more effective than either treatment alone.
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