On the Concept of Low-Dose "Metronomic" 

Anti-Angiogenic Chemotherapy

Exploiting COX-2 Inhibitors As Anti-Angiogenic Drugs for Combination Metronomic Chemotherapy.

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.

Thus 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 3.

This may 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 3

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.

In 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, lower panel).

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 mortality.


Conclusions

Robert S. Kerbel, Ph.D. University of Toronto

Metronomic Dosing of Cytotoxic Drugs in Mice

Commentary, J Clin Invest, April 2000

G. Klement , Ontario Canada on Metronomic Dosing

2nd Int'l Conf Mechanisms of Cell Death & Disease, 6/01

Patient Perspective from Sybil Brabner

Discussion of Sybils's protocol and some references

Differences in Therapeutic Indexes

Clinical Cancer Res 1/02

Low Dose Oral Methotrexate & Cycophosphamide

Annals of Oncology, 2/02

Dana Farber has Metronomic Type Trial

Boston Hospital, 5/03

Metronomic Trial Update
Hyperthermia & Metronomic Chemo:Rat Mammary Ca

Intl J Hyperthermia, 3/03

Anti-ANGIOGENIC Basis:Metronomic Chemo

Nature Reviews Cancer, 6/04

References
Targeting Angiogenesis w/Integrative Therapies
High-Dose celecoxib and metronomic "low-dose
AVASTIN Alert Issued

August 13, 2004


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