Exploiting COX-2 Inhibitors As Anti-Angiogenic Drugs for Combination
A recent exciting development has made it
possible to evaluate the concept of low dose metronomic anti-angiogenic
chemotherapy in the clinic,namely the discovery that cyclooxygenase-2 (COX-
2)is involved in angiogenesis and that safe,commercially available drugs such
as Celebrex a selective COX-2 inhibitor demonstrate anti-angiogenic
effects after oral or intraperitoneal administration in ivo in various preclinical
models,including inhibition of PC3 prostate cancer growth and angiogenesis
in nude mice.
Studies have shown that COX-2 is upregulated in activated
endothelial cells of tumor vessels as well as the stromal cells and tumor cells
of virtually all types of human carcinoma,including prostate cancer.
COX-2 inhibitors have the potential to block tumor growth by various direct
effects such as induction of tumor cell apoptosis as well as indirectly,by
inhibiting angiogenesis,and recent results suggest the latter may be the more
important of the two mechanisms.
Moreover,there is evidence that COX-2
inhibitors can block VEGF expression
,and thus function,as de facto VEGF
antagonists,including,interestingly,in prostate cancer cells.
On the basis of these results we have initiated experiments to evaluate the
effects of daily oral Celebrex combined with low dose continuous taxol on
human prostate cancer xenografts. Treatment was initiated when the tumors had reached >400 mm
explain the failure of Celebrex treatment alone to block tumor growth as we
have since learned from Searle/Pharmacia that Celebrex is usually not
effective if treatment is initiated once tumors are larger than 100 S 150 mm
However,daily oral Celebrex at a
dose of 75 mg/kg,when combined with 0.5 mg/kg taxol given intraperitoneally
three times a week,demonstrated significant prolongation of survival.
contrast,taxol alone had no effect.These results have encouraged us to
examine the impact of Celebrex in combination with other drugs such as
vinblastine or oral cyclophosphamide,and beginning treatment at an earlier
stage,as well as assessing effects on metastatic disease.
We have also obtained similar results using human breast cancer cell lines,
but in these cases they were previously selected in vitro or in vivo for very high
levels of acquired resistance (e.g.50 S 100 fold)to the chemotherapeutic drug
that was used for the low dose therapy .Figure 3 shows the results of such an
experiment using vinblastine and DC101 against a multidrug resistant P-
glycoprotein positive variant of the human MB-MDA-231 breast cancer.
Similar experiments using i)Cisplatinum and DC101 to treat a Cisplatinum
resistant variant of the MB-MDA-231 breast cancer and ii)Adriamycin and
DC101 to treat Adriamycin resistant variant of MB-MDA-231 are shown in
Figures 4.In these experiments the cells were injected orthotopically into
the mammary fat pads of SCID mice.
With respect to host toxicity
vinblastine has the safest profile,as assessed by using weight loss of the
mice as a surrogate marker.
Interestingly,while all of the chemotherapeutic agents used in our drug
resistant experiments (Cisplatinum,vinblastine,taxol,adriamycin and
cyclophosphamide)produced similar degre of tumor growth suppression,
it was only vinblastine that did so with minimal host toxicity (Figure 3,
Supporting the need to find the minimum effective dose is the
comparison between 1mg/kg twice weekly and 2mg/kg twice weekly
cisplatinum.While initially 2mg/kg appears to be more effective,with
time,1mg/kg achieves the same effect with significantly less morbidity and
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