An Old Antibiotic for Metastatic Bone Cancer

Dr. Weeks’ Comment: Remember the dentist or pediatrician warning you not to give your children tetracycline because it might mottle your kid’s teeth? Well that is because tetracycline antibiotics interrupt normal bone function so … some smart scientist starting wondering about whether drugs in this class of antibiotics might help reduce or prevent metastatic disease in bone!  Isn’t it gratifying when people think intelligent thoughts!      

Now we know that Doxycycline, a tetracycline antibiotic drug commonly used to treat infection, has specific anti-Myc, anti-tumor activity which applies to cancer which spread to bone. Numerous studies have shown that doxycycline induces apoptosis (programmed cell death) and reduces cancer cell proliferation by down-regulating these Myc genes in cancer cells including metastatic disease in bone.

What cancers are effected?  Well the following have been studied: Breast cancer, non-small cell lung cancer, liver cancer, pancreatic cancer and bone cancers have shown positive response to doxycycline use but the principles apply to cancer in general. Here are some articles to consider and to share with your oncologist.

“…..tetracycline and derivatives of tetracycline, namely doxycycline and minocycline, also induced cytotoxicity. The effective concentrations are relatively high for plasma, but are clinically achievable in the bone, since tetracyclines are osteotropic…”  

“…The natural osteotropism of tetracyclines would allow them to be highly effective in the inhibition of MMPs produced by osteoclasts or tumor cells in the bone…”

Now that is just plain smart medicine! 

 

Anticancer Drugs. 2003 Nov;14(10):773-8.

Doxycycline and other tetracyclines in the treatment of bone metastasis.

Source

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Abstract

The tetracycline family includes tetracycline, doxycycline and minocycline, all of which have been used as antibiotics effectively for decades. New uses emerged for these compounds after their effect on mitochondrial function was discovered. Cytostatic and cytotoxic activity of these compounds was shown against cell lines of various tumor origins. In addition, tetracyclines and chemically modified tetracyclines inhibit the activity of several matrix metalloproteinases (MMPs). Given the importance of these enzymes in tumor cell invasion and metastatic ability, the potential use of tetracyclines in cancer therapy needed to be investigated. Col-3, a chemically modified tetracycline, is now the subject of clinical trials in cancer patients. However, the potential of tetracyclines in cancer therapy takes on an added dimension in the bone. MMPs have been shown to be important mediators of metastasis formation in the bone, contributing largely to the morbidity of breast cancer and prostate cancer patients. The natural osteotropism of tetracyclines would allow them to be highly effective in the inhibition of MMPs produced by osteoclasts or tumor cells in the bone. This hypothesis has now been confirmed by experimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis. This effect is likely due to a combination of multiple roles of doxycycline, including MMP inhibition and a negative effect on osteoclast differentiation and survival. These encouraging results have now paved the way for an ongoing trial of doxycycline in early combination therapy for breast cancer and prostate cancer patients.

 

The Effect of Doxycycline on Bone Turnover and Tumor Markers in Breast Cancer (BC) Patients with Skeletal Metastases Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3198Author(s):S. K. Dhesy-Thind, J. Julian, R. Tozer, P. Ellis, A. Arnold, G. Singh, M. Levine

 

Abstract

 

Background: Doxycycline is a tetracycline analogue which is osteotropic with high affinity for mineralized bone. In experimental systems, it has anti-cancer effects including inhibition of matrix metallo proteinases, anti-angiogenic activity and a cytostatic effect on cancer cells. Methods: 17 patients with newly diagnosed bone metastases from BC, and no prior bisphosphonate therapy were treated with Doxycycline 100 mg po bid for 3 months. Treatment was discontinued for disease progression or unacceptable toxicity. Bone scans and serum bone markers [N-telopeptide (NTx – Osteomark NTx Serum) and bone specific alkaline phosphatase (BAP – Metra BAP)] were measured as markers of bone turnover and PTHrP as a marker of tumor progression at baseline and following 12 weeks of therapy. Patients subsequently received bisphosphonate therapy. The primary outcome was a 50% relative decrease in serum bone markers.

Results: 12 patients were evaluable for response, 3 patients discontinued therapy due to toxicity and were non-evaluable, and results are pending for 2 others. Median age was 62.5 years and 4 patients had other metastatic sites. 3 patients received concurrent chemotherapy and 9 patients hormonal treatment. There were no cases of pathological fractures or hypercalcemia. Results of the bone markers studies are shown below. 11 of 12 patients had normal serum NTx values and 5/12 had normal BAP at baseline despite extensive bone metastases. PTHrP levels in 9 of 12 patients either declined or remained at the same level after 12 weeks.

Conclusions: Although Doxycycline for 3 months was associated with a drop in serum bone markers in some patients, it failed to satisfy the pre-specified outcome measure of a 50% decrease. A possible explanation is the lack of responsiveness of the outcome measure. Our study demonstrated the feasibility of administration of long-term Doxycycline. Further studies evaluating this agent are warranted.

 

 

Invasion Metastasis. 1997;17(6):312-22.

Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by human bone-metastasizing cancer cells.

Source

Hamilton Regional Cancer Centre, McMaster University, Hamilton, Canada.

Abstract

Bone metastases are a common complication in prostate and breast cancer patients. It leads to extensive morbidity and eventually mortality. Matrix metalloproteinases are implicated in various steps of development of metastasis, through their ability to degrade the extracellular matrix. Increased matrix metalloproteinase activity of tumor cells has been associated with a higher metastatic potential. Inhibitors of metalloproteinases have been shown to effectively reduce or prevent the formation of metastases. The family of tetracyclines is able to inhibit matrix metalloproteinase activity through chelation of the zinc ion at the active site of the enzyme. Using tumor cell lines relevant to bone metastases, i.e. PC-3, MDA-MB-231, Hs696, B16/F1, we showed that tetracycline and derivatives of tetracycline, namely doxycycline and minocycline, also induced cytotoxicity. The effective concentrations are relatively high for plasma, but are clinically achievable in the bone, since tetracyclines are osteotropic. All four bone-metastasizing tumor cells produced and secreted various matrix metalloproteinases. Doxycycline was able to inhibit the activity of 72- and 92-kDa type IV collagenase secreted by bone-metastasizing cells by 79-87%. These characteristics could make tetracycline a unique candidate as a therapeutic agent to prevent bone metastases in cancer patients with a high likelihood for development of bone metastasis. Studies using animal models of experimental bone metastasis will be necessary to confirm this.

Int J Cancer. 2002 Mar 10;98(2):297-309.

Inhibition of cell proliferation, invasion, tumor growth and metastasis by an oral non-antimicrobial tetracycline analog (COL-3) in a metastatic prostate cancer model.

Source

Sylvester Comprehensive Cancer Center and Department of Urology, University of Miami School of Medicine, Miami, FL 33101, USA. BLOKESHW@med.miami.edu

Abstract

Antibiotic forms of tetracycline exhibit antitumor activity in some tumor models. However, their low in vivo efficacy and associated morbidity limit their long-term application in cancer therapy. This report appraises the efficacy of doxycycline (DC) and non-antimicrobial, chemically modified tetracyclines (CMTs) against prostate cancer. Both DC and several CMTs inhibited prostate tumor cell proliferation in vitro. Some of the CMTs were significantly more potent than DC. One of the CMTs, 6-deoxy, 6-demethyl, 4-de-dimethylamino tetracycline (CMT-3, COL-3), was the most potent inhibitor (50% inhibition dose [GI(50)] < or = 5.0 ,microg/ml). Exposure of tumor cells to CMT-3 induced both apoptosis and necrosis. Mitochondrial depolarization and increased levels of reactive hydroxyl radicals were also observed in cells treated with CMT-3. Cell cycle arrest at the G(0)/G(1) compartment was observed in CMT-3- and DC-treated cells. DC and CMTs also inhibited the invasive potential of the tumor cells in vitro, from 10% (CMT-6) to >90% (CMT-3). CMT-3 and DC decreased matrix metalloproteinase (MMP)-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 secretion in treated cultures and inhibited activity of secreted MMPs, CMT-3 was a stronger inhibitor. Daily oral gavage of DC and CMT-3 inhibited tumor growth and metastasis in the Dunning MAT LyLu rat prostate tumor. Decreases in tumor growth (27-35%) and lung metastases were observed (28.9 +/- 15.4 sites/animal [CMT-3-treated] versus 43.6 +/- 18.8 sites/animal [DC-treated] versus 59.5 +/- 13.9 [control]; p < 0.01]. A delay in tumor growth (27 +/- 9.3%, p < 0.05), reduction in metastases (58 +/- 8%) and decrease in tumor incidences (55 +/- 9%, CMT-3-treated) were also observed, when rats were predosed for 7 days. No significant drug-induced morbidity was observed in any of the animals. These results, along with a recently concluded clinical trial, suggest a potential use of CMT-3 as an oral, nontoxic drug to treat metastatic prostate and other cancers.

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Dr. Weeks’ Comment: Remember the dentist or pediatrician warning you not to give your children tetracycline because it might mottle your kid’s teeth? Well that is because tetracycline antibiotics interrupt normal bone function so … some smart scientist starting wondering about whether drugs in this class of antibiotics might help reduce or prevent metastatic disease…
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