• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Compounding Antiangiogenic Cancer Therapy for Animals

Posted on: Tuesday, 3 May 2005, 03:00 CDT

Angiogenesis is defined simply as the development of new blood vessels. In spite of the heterogeneity of cell types across various cancers, all tumor cells have a uniform vulnerability: the requirement for oxygen and nutrients. Tumor cells multiply and thrive by utilizing oxygen and other nutrients that arrive in blood delivered by blood vessels. Tumors may initially survive by diffusion of oxygen and nutrients from nearby vessels, but to maintain growth, blood vessels must be in close proximity. In fact, research by Dr. Isaiah Fidler at The University of Texas M. D. Anderson Cancer Center revealed that tumor cells cannot survive unless they are within 150 microns of a bloodvessel.1

Pathologic angiogenesis, or the process by which a malignant tumor develops its own blood vessels, is the primary means by which tumors grow and spread. When a tumor "senses" that available nutrients are no longer suitable to promote growth, growth factors are switched on, facilitating the growth of new blood vessels that will migrate out and connect to existing blood vessels. By stopping the signals that initiate growth of these vessels, tumor growth can be arrested. If this arrest starts early enough, angiogenesis can be interrupted even while the tumor is still undetectable. Researchers have determined that early inhibition of angiogenesis can result in prevention of tumor growth beyond the 60- to 100-cell stage.2

Angiogenesis is also vital to the growth of successful metastases. Therefore, long-term inhibition of angiogenesis could result in cancer becoming a chronic disease instead of a life- threatening disease. Angiogenesis can occur through a variety of molecular signaling methods, and "starving" a tumor by inhibiting this signaling has become the focus of antiangiogenic drug therapy strategies for treating cancer. Many of the drugs used in antiangiogenic therapy are human labeled drugs approved for indications other than cancer. As antiangiogenic properties may occur at lower doses than those for which the drug is indicated, compounding is frequently necessary to obtain therapeutic doses of these drugs for animal patients. This article is intended to provide the compounding pharmacist with an understanding of the principles of antiangiogenic therapy and to describe current protocols and drugs used in veterinary medicine for antiangiogenic treatment.

Table 1. Mechanisms of Antiangiogenic Drugs.

Table 2. Drugs Used for Antiangiogenic Therapy in Animal Patients.

Overview of Angiogenesis

When the cellular environment surrounding the tumor becomes hypoxic, blood vessels form in response to proangiogenic factors such as vascular endothelial growth factor (VEGF). For a new vessel to develop, multiple steps must be successfully completed. The extracellular matrix (ECM) must be remodeled, the endothelial cells must migrate and proliferate, a lumen must form, and, finally, anastomosis to other blood-containing vessels must occur. While discussion of each of the complex steps of angiogenesis is too broad for the scope of this article, the compounding pharmacist should be familiar with the major growth and transcription chemical signals that "switch on" angiogenesis.

Matrix metalloproteinases (especially MMP-2 and MMP-9) are enzymes that are secreted to degrade the ECM. Any new blood vessels formed by angiogenesis can migrate only after the ECM is degraded. MMP-2 and MMP-9 have long been associated with tumor progression and metastasis.6-8 Although mechanisms of MMP inhibition remain obscure, n-3 omega fatty acids have been shown to be very effective MMP inhibitors, an action that is thought to be mediated through inhibition of serum lactate formation.9 Collagenase is another proteinase enzyme responsible for breaking down local barriers to vessel development. Collagenases can function only in the presence of cations such as zinc and calcium. Therapies targeted at chelating these ions decrease the activity of collagenase, thereby inhibiting angiogenesis. Tyrosine kinase is another important enzymatic catalyst of angiogenesis and facilitates the stabilization and maturation of newly formed tumor capillaries. Finally, cyclooxygenase 2 (COX-2) is overexpressed in many tumors and is correlated with increased vascularity of tumors.10 Nonsteroidal anti- inflammatory drugs (NSAIDs) that selectively inhibit the COX-2 receptor have played a valuable role in tumor antiangiogenic therapy for animal patients.

Table 3. Compounds Used for Antiangiogenesis Therapy in Animals.

Antiangiogenic agents are directed at the budding endothelial cells (metronomic chemotherapy), at the surrounding stroma (to inhibit invasion by vascular growth-promoting enzymes such as MMP and collagenase inhibitors), or at growth and transcription factors that are released by the tumor to stimulate angiogenesis. Table 1 lists the mechanisms of action for drug classes used to inhibit angiogenesis.

Advantages of Antiangiogenic Therapy

Antiangiogenic therapies have unique advantages over conventional chemotherapy regimens. Antiangiogenic therapies are not as toxic as conventional chemotherapy because they are not cytotoxic in nature. Moreover, in contrast with systemic chemotherapy, many antiangiogenic therapies are metronomic in nature (ie, administered over long periods at low doses). Endothelial cells, the key to angiogenesis, are not as genetically unstable as tumor cells, thereby making antiangiogenic therapies less likely to develop resistance. As safe and apparently effective as antiangiogenic therapies currently are, however, tumors are very likely to develop alternative methods of inducing angiogenesis, thereby circumventing antiangiogenic activity.

Because cytotoxicity is not the primary mechanism of antiangiogenic cancer therapy, objective assessment of therapeutic success must not rely on traditional endpoints. Specifically, instead of attempting to put the tumor in regression, the disease can be put into "remission" by keeping tumor burden and growth static. Nongrowing and noninvasive tumors can be fairly innocuous. When residual tumor burden is measurable, this type of therapeutic approach treats cancer more as a chronic disease than as a curable or life-threatening condition.

Antiangiogenic Drug Therapies

While several antiangiogenic human therapies are either newly approved or currently in clinical trials, most antiangiogenic therapy for veterinary patients is accomplished through the use of N1SAIDs. Interestingly, thalidomide has proven to be a very effective antiangiogenic agent in humans, but animal use of thalidomide is strictly prohibited in the United States. Other agents used for veterinary antiangiogenic therapies include doxycycline and minocycline, cyclophosphamide and chlorambucil, and the omega-3 fatty acids. Protocols for each drug are described in Table 2.

Compounding for Antiangiogenic Therapy

As previously mentioned, most drugs currently utilized for veterinary antiangiogenesis therapy are approved only for use in humans and are consequently provided in dosage forms that are either costprohibitive or dosing-prohibitive for animal patients. For example, the lowest commercially available strength of piroxicam is 10 mg, which is provided in a capsule. Piroxicam is dosed at 0.3 mg/ kg for antiangiogenesis, and thus the smallest patient treatable with a 10-mg capsule is 33 kg or 73 lbs. Most veterinary cancer patients fall far below this weight, necessitating compounding of a more appropriate dosage form of piroxicam. Moreover, as all NSAIDs have a very narrow therapeutic index in animal patients, exact dosing is imperative, as the animal will likely receive metronomic antiangiogenic therapy for the rest of its life. Likewise, novel antiangiogenic therapies approved for humans (eg, angiostatin, endostatin, imatinib mesylate, gefitinib) will ultimately prove to be beneficial in animal antiangiogenesis, and compounding pharmacists can play a valuable role in reformulating cost- prohibitive human-approved products into more appropriate dosage forms for animal cancer patients. Remarkably, many animal patients develop cancers at the same time, sometimes of the same type, as their guardian owners. With careful collaboration between the human oncologist, the veterinary oncologist, and the compounding pharmacist, optimal therapy for both owner and pet can be provided by drawing upon successes from experience in both human and veterinary medicine. While all potential compounds for animal antiangiogenic therapy cannot be presented in this article, Table 3 is presented as a catalyst for thought on opportunities to compound for animal patients requiring antiangiogenic cancer therapy.

Summary

Compounding pharmacists can play a vital role in providing antiangiogenic cancer therapy for animal patients, thereby facilitating the shift in perspective of cancer from a life- threatening diagnosis to a manageable chronic disease. Understanding key etiologic, pathologic, and therapeutic points can facilitate the pharmacist's participation in the veterinary care triad for cancer therapy. Compounding pharmacists well versed in current concepts for both human and veterinary antiangiogenic therapy will maximally contribute to positive outcomes in veterinary cancer care.

References

1. Fidler IJ. Angiogenic heterogeneity. Regulation of neoplastic angiogenesis by the organ microenvironment\. J Natl Cancer lnst2001; 93(14):1040-1041.

2. Hagedorn M, Bikfalvi A. Target molecules for anti-angiogenic therapy: From basic research to clinical trials. Crit Rev Oncol Hematol 2000; 34(2):89-110.

3. Rajkumar SV. Current status of thalidomide in the treatment of cancer. Oncology 2001; 15(7): 867-874.

4. Fournier P, Boissier S, Filleur S et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62(22): 6538-6544.

5. Wood J, Ronjean K, Ruetz S et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 2002; 302(3): 1055-1061.

6. Figg WD, Dahut W, Duray P et al. A randomized phase Il trial of thalidomide, an angiogenesis inhibitor, in patients with androgen- independent prostate cancer. Clin Cancer Res 2001; 7(7):1888-1893.

7. Hidalgo M, Eckhardt SG. Development of matrix metalloproteinase inhibitors in cancer therapy. J Natl Cancer lnst 2001; 93(3): 178-193.

8. McCloskey EV, Guest JF, Kanis JA. The clinical and cost considerations of bisphosphonates in preventing bone complications in patients with metastatic breast cancer or multiple myeloma. Drugs 2001; 61 (9): 1253-1274.

9. Ogilvie G. Matrix metalloproteinases and their inhibitors. In: Proceedings of the Forum of the American College of Veterinary Internal Medicine; 2002; Fort Collins, CO.

10. Subongkot S, Frame D, Leslie Wet al. Selective cyclooxygenase- 2 inhibition: A target in cancer prevention and treatment. Pharmacotherapy 2003; 23(1): 9-28.

Gigi Davidson, BSPh, RPh, FSVHP, DICVP

North Carolina State University College of Veterinary Medicine

Raleigh, North Carolina

Address correspondence to Gigi Davidson, BSPh, RPh, FSVHP, DICVP, Director of Clinical Pharmacy Services, North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606. E- mail: gigi_davidson@ ncsv.edu

Copyright International Journal of Pharmaceutical Compounding May/ Jun 2005

Source: International Journal of Pharmaceutical Compounding

More News in this Category