Advertisement
 

doctorslounge.com

 
Powered by
Careerbuilder

 

                    Home  |  Forums  |  Humor  |  Advertising  |  Contact
   Ask a Doctor

   News via RSS

   Newsletter

   Pharmacy

   News

 

 Conferences


   CME

   Forum Archives

   Diseases

   Symptoms

   Labs

   Procedures

   Drugs

   Links
   Specialties

   Cardiology

   Dermatology

   Endocrinology

   Fertility

   Gastroenterology

   Gynecology

   Hematology

   Infections

   Nephrology

   Neurology

   Oncology

   Orthopedics

   Pediatrics

   Pharmacy

   Primary Care

   Psychiatry

   Pulmonology

   Rheumatology

   Surgery

   Urology

   Other Sections

   Membership

   Research Tools

   Medical Tutorials

   Medical Software

 

 Headlines:

 
 

Back to Pharmacology Articles

 Sunday, 2 March 2003 05:50 PM GMT

Tetracyclines (TM) new uses
 
 

Tetracyclines possess properties that are independent of their antimicrobial characteristics e.g. arthritis.

 
 

tellfrnd.gif (30x26 -- 1330 bytes)send to a friend
 
prntfrnd.gif (30x26 -- 1309 bytes)printer friendly version
 
 
  Related
 
 

Celebrex may not protect against ulcer
Ibuprofen, aspirin combo bad for heart?

 
   
 

Tetracyclines are primarily bacteriostatic broad-spectrum antimicrobial agents, they are thought to exert their effect by the inhibiting protein synthesis. However, in the early 1980?s, tetracyclines have surprised researchers with unexpected properties that are entirely independent of their antimicrobial characteristics.

Researchers have since sought to find out the potential role of these novel properties of the old well known class of antibiotics in diverse types of diseases. The clinical applications and the pharmaceutical uses of these compounds appears to be emerging in the coming few years.

Tetracyclines at low doses were found to interfere with the production of prostaglandins and leukotrienes (1-3), scavenges oxygen radicals (4), interferes with the expression of nitrous oxide synthase (5), and enhances natural inhibitors of matrix metalloproteinases (6,7). after this novel discovery nonantimicrobial chemically modified tetracyclines (CMT) were prepared and widely investigated in different type of diseases.

Worth noting, low dose doxycycline, sub-antimicrobialdoxycycline (Periostat), is the first FDA-approved matrix metalloproteinase inhibitor or collagenase inhibitor for any connective tissue disease.

Matrix Metalloproteinases (MMPS)

These are a family of very important enzymes that are involved in many physiological and pathological process in our body. Embryological development, growth morphological changes, ovulation, pregnancy  and wound healing are the processes where their physiological role can be studied. Atherosclerosis, aortic aneurysms, corneal ulcers of the eye, inflammation, tumour invasion and metastasis reflects their involvement in pathological processes which has been turned out as major research target to  find out different therapeutic interventions and drug development for treatment of these diseases.

What is the key mechanism involved in all these diverse processes and in what way are tetracyclines related?

All these processes are mediated by degradation and breakdown of extracellular matrix proteins (collagens, glycoproteins and proteoglycans). This degradation is mediated by this family of enzymes (matrix metalloproteinases). These are very potent enzymes that are highly regulated by transcriptional (at the mRNA level) and posttranscriptional mechanisms( protein level). It is the main substrate for the nonantimicrobial action of tetracyclines. 

advertisement.gif (61x7 -- 0 bytes)
 

Are you a doctor or a nurse?

Do you want to join the Doctors Lounge online medical community?

Participate in editorial activities (publish, peer review, edit) and give a helping hand to the largest online community of patients.

Click on the link below to see the requirements:

Doctors Lounge Membership Application


1- Inflammatory processes

Tetracyclines in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic disorder that causes pain, swelling, stiffness, and loss of function in the joints. A major step in the parthenogenesis of rheumatoid arthritis (RA) is the destruction of the extracellular matrix (ECM) of cartilage, bone, and soft tissues through the release of matrix-degrading enzymes ,matrix metalloproteinases (MMPs). MMPs are important mediators of tissue destruction in rheumatoid arthritis and other chronic inflammatory and non-inflammatory arthropathies (8-10). Different studies have proved the efficacy of  CMT in improving diverse forms of arthritis.

Periodontal disease (a disease of the gums).

Researchers have found that collagenase enzyme level is 4 times higher in some populations who show higher risk for periodontal disease. CMTs have been proved to be effective treatment of these patients. Dentists also use tetracycline periodontal fibers are placed in the inflamed mouth areas in part due to its antibacterial action and as antinflamatory (6,11).

2- Cancer development

Matrix metalloproteinases being enzymes responsible for remodelling and degradation of the extracellular matrix (ECM), they help tumour cells to create new space  for their own growth as well as forming new blood vessels important for their feeding. In this way they also can sneak into blood vessels reaching the circulation. Modified tetracyclines as inhibitors for collagenase (major component of CT matrix) and other metalloprotienases have been studied and proved to be useful in treating cancer and decreasing the metastasic potentials of cancer cells in conjunction to the treatment of the primary disease by conventional methods(12-14). Recently, doxycycline was found to regulate the level of expression of different genes regulationg cell cycle proliferation and migration.

SPARC (secreted protein acidic and rich in cysteine)/BM40/Osteonectin is a matricellular protein with multiple effects on cell behaviour. In vitro, its major known functions are anti-adhesive and anti-proliferative, and it is associated with tissue remodelling and cancer in vivo. SPARC is overexpressed in many cancers, including breast cancer (found to be involved mainly in controlling cell proliferation), in melanoma (controlling cell proliferation and migaration as well), and in glioma controlling cell migration(15).

?Growth-inhibitory effect of doxycycline and induction of apoptosis mediated by caspase 3 on CCRF-CEM, a T-lymphoblastic human leukemic cell line suggest that this well tolerated oral drug has the potential to be of value   in treatment of leukaemia(16).

?Caspase 3, poly(ADP-ribose) polymerase (PARP), and BCL2 which are apoptotic factors have been found to be upregulated bye doxycycline in neuroblastoma cell lines(17).

Other Medical conditions

Aortic aneurysms

Aortic aneurysm is a life-threatening disease, and again is related to the excess collagenase in the walls of these blood vessels, thinning out the wall, causing expansion .CMTs block these enzymes and may stabilise the aneurysm and may prevent urgent surgical need in elderly atherosclerotic patients.

Diabetes

These novel properties directed investigators to try Tetracyclines as inhibitors for collagenase in the blocking diabetes induced retinopathy and atherosclerosis with promising results. What is very interesting is that in vivo animal studies have shown that retinal detachment is mediated by activation of caspase-3, -7, and -9 and PARP which have been shown to be regulated by doxycline in different cell lines(18).

CMTs are a very interesting clinical and research area for future studies.

References

1.        Pruzanski W, Greenwald RA, Street IP, et al. Inhibition of enzymatic activity of phospholipases A2 by minocycline and doxycycline. Biochem Pharmacol 1992;44(6):1165-70 2.        ElAttar TM, Lin HS, Shultz R. Effect of minocycline on prostaglandin formation in gingival fibroblasts. J Periodontal Res 1988;23(5):285-6

3.        Golub LM, McNamara TF, D'Angelo G, et al. A non-antibacterial chemically-modified tetracycline inhibits mammalian collagenase activity. J Dent Res 1987;66(8):1310-4 4.        van Barr HM, van de Kerkhof PC, Mier PD, et al. Tetracyclines are potent scavengers of the superoxide radical. (Letter) Br J Dermatol 1987;117(1):131-2

5.        Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA 1996;93(24):14014-9

6.        Golub LM, Ramamurthy N, McNamara TF, et al. Tetracyclines inhibit tissue collagenase activity: a new mechanism in the treatment of periodontal disease. J Periodontal Res 1984;19(6):651-655

7.        Smith RL, Schurman DJ, Kajiyama G, et al. The effect of antibiotics on the destruction of cartilage in experimental infectious arthritis. J Bone Joint Surg [Am] 1987;69(7):1063-8

8.        Krane SM. Mechanisms of tissue destruction in rheumatoid arthritis. In: McCarty DJ, Koopman WJ, eds. Arthritis and allied conditions: a textbook of rheumatology. 12th ed. Philadelphia: Lea & Febiger, 1993:763-9

9.        Zvaifler NJ, Firestein GS. Pannus and pannocytes: alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum 1994;37(6):783-9

10.     Ishiguro N, Ito T, Ito H, Iwata H, Jugessur H, Ionescu M, Poole AR. Relationship of matrix metalloproteinases and their inhibitors to cartilage proteoglycan and collagen turnover: analyses of synovial fluid from patients with osteoarthritis. Arrthritis Rheum 1999;41:129?36

11.     Golub LM, Goodson JM, Lee HM, et al. Tetracyclines inhibit tissue collagenases: effects of ingested low-dose and local delivery systems. J Periodontol. 1985;56(suppl):93-97.

12.     Johansson N, Airola K, Gr?man R, Kariniemi A-L, Saarialho-Kere U, K??i V-M. (1997) Expression of collagenase-3 (matrix metalloproteinase-13) in squamous cell carcinomas of the head and neck. Am J Pathol 151:499-508.

13.     Bramhall, S. R., Stamp, G. W., Dunn, J., Lemoine, N. R., and Neoptolemos, J. P. (1996). Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease. Br. J. Cancer 73: 972-978

14.     Wang, M., Liu, Y. E., Greene, J., Sheng, S., Fuchs, A., Rosen, E. M., and Shi, Y. E. (1997). Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14: 2767-2774.

15.     Dhanesuan N, Sharp JA, Blick T, Price JT, Thompson EW.Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition.Breast Cancer Res Treat. 2002 Sep;75(1):73-85

16.     Iwasaki H, Inoue H, Mitsuke Y, Badran A, Ikegaya S, Ueda T.Doxycycline induces apoptosis by way of caspase-3 activation with inhibition of matrix metalloproteinase in human T-lymphoblastic leukemia CCRF-CEM cells. . .  Journal of Laboratory and Clinical Medicine, Volume 140, Issue 6, Pages 382-386

17.     Zhonghua Bing Li Xue Za Zhi .Effects of tetracycline-controlled antisense bcl-2 expression on the growth and apoptosis of human neuroblastoma cell line SK-N-MC.. 2002 Apr;31(2):135-9.
PMID: 12419161

18.     Zacks DN, Hanninen V, Pantcheva M, Ezra E, Grosskreutz C, Miller JW.Caspase activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1262-7.

Article reviewed by:

Dr. Safaa Mahmoud, M.D.

 

 advertisement.gif (61x7 -- 0 bytes)

 

 



We subscribe to the HONcode principles of the HON Foundation. Click to verify.
We subscribe to the HONcode principles. Verify here

Privacy Statement | Terms & Conditions | Editorial Board | About us
Copyright 2001-2012 DoctorsLounge. All rights reserved.