Re:Re:Doxycycline Vitamin C Anti Cancer Synergy

[문형철]

BEYOND REASON

Doxycycline Vitamin C Anti-Cancer Synergy

Eradicates Cancer Stem Cells

I was simply astounded by a publication appearing last week in Oncotarget  on anti-cancer synergy of Doxycyline and vitamin C.(1)  This is a really huge breakthrough in cancer research,  in our quest for effective non-toxic cancer treatment.  Working with MCF7 Breast cancer cell cultures, Lisanti’s group showed  the combined use of Doxycycline and Vitamin C  was a “lethal metabolic strategy for eradicating cancer stem cells”.(1)

Doxycycline

Doxycline is a safe common antibiotic used for 50 years. I have seen patients coming into the office  on doxycycline for months or even years for treatment of acne or rosacea.  Likewise Vitamin  C is about as safe as a substance as you can get.  Clinical trial safety study on relapsed B-Cell Lymphoma patients receiving 75 grams of Vitamin C Intravenously reported no adverse effects.(47)  Left image doxycycline courtesy of National Library of Medicine

Cancer Stem Cells Escape from Doxycycline Become Purely Glycolytic Phenotype

In an elegant study, Lisanti’s group created Doxycycline resistant cancer stem cells by successive passage of the cells through higher doses of Doxycycline treatments.   Most of the cells were killed by the Doxycycline.  However the few surviving cells were then allowed to multiply and repopulate, and were again treated with higher doses of doxyxycline.  This process was repeated until final cells were indeed Doxycyline resistant, they were immune to the antibiotic.

Lisanti’s group then did next generation molecular studies on the Dox-R cancer stem cells showing they had assumed a purely glycolytic phenotype.

Above left image Figure 12 from Lisanti (1)

The Dox-Resistant cancer cells were now sensitive to eradication with metabolic perturbation from high dose vitamin C.  Vitamin C acts as a glycolysis inhibitor, by targeting (GAPDH) Glyceraldehyde 3-phosphate dehydrogenase, 6th step in glycolysis.   Vitamin C also and depletes the (NAD) nicotinamide adenine dinucleotide pool.  High dose IV vitamin C easily reached serum concentrations for these lethal effects in the clinical setting.

A few other drugs and natural substances were also effective, namely Berberine, Chloroquin, Atovaquone (45-46), Niclosamide etc. )  The authors state,

“understanding the metabolic basis of Doxycycline-resistance has ultimately helped us to develop a new synthetic lethal strategy, for more effectively targeting Cancer Stem Cells (CSCs). ”  

Left Image figure 10 from Lisanti(1)  Fig A effect of 2DG (2-de-oxyglucose) on both plain MC7 breast cancer stem cells and Dox-resistant cells.  Fig B: effect of Vitamin C on Dox Resistant breast cancer stem cells.  100% (complete) cell death at 500 micromolar=0.5 millimolar.

Metformin and Cancer Stem Cells

Lisanti’s group found Berberine effective against cancer stem cells.  Metformin is another agent with similarities to berberine which targets cancer stem cells by inhibiting Complex One in the mitochondrial electron transport chain.  Working with a pancreatic cancer cell model, Dr Patricia Sanchez in Cell Metabolism 2015 found that Metformin was effective as a cancer stem cell agent. (44) Dr Sanchez found that cancer stem cells rely on OXPHOS (oxidative Phosphorylation) while non-cancer stem cells were highly glycolytic. (44)  Metformin treatment killed most of the cancer stem cells.  However resistant stem cell clones emerged with a glycolytic phenotype.  As noted above, this conversion to a glycolytic phenotype is exactly what Lisanti’s group found when treating breast cancer stem cells with Doxycyline.   This glycolytic phenotype was then vulnerable to lethal effects of  high dose IV vitamin C serving as glycolysis inhibitor.

Dr Sanchez was disappointed to find that pancreatic tumors developed resistance to Metformin progressed in a more aggressive form in cancer xenografts.  On the other hand, treatment with Menadione (Vit K3), which both inhibited complex one and increased ROS, was lethal to the cancer xenografts without inducing resistant cell types.

Salinomycin 3BP Bogata Colombia

Salinomycin, another promising cancer stem cell agent, was used in an anecdotal case report from Bogata Colombia by Jason Williams MD and Marc Rosenberg MD.  Twenty One rounds of IV Salinomycin and 3-bromopyruvate was given on alternate days to a patient with small cell lung cancer.  Follow up  CAT scan showed disappearance of the patient’s lung mass.  Although results were encouraging, further Salinomycin trials in 20 or so additional patients provided only temporary remission from cancer, with later emergence of resistant cell types.(personal communication Jason Williams MD)   Following these disappointing results, research efforts were re-directed towards other modalities such as image guided ablation and immunotherapy.   Perhaps results would have been better with the use of other combination drugs such as Doxycycline, High Dose IV Vitamin C, Metformin, Atovaquone, Artesunate, Alpha Lipoic Acid  etc.

This highlights the dangers of Cancer Stem Cell treatments which merely induce resistant cancer cell types which are more aggressive and more difficult to treat.  Another problem is knowing when the treatment has eradicated all the cancer stem cells.  At the present time we don’t have a good method for determine this, and so we don’t know when to stop treatment.   If treatment is stopped too soon, then resistant cancer stem cells are left behind to induce a relapse.  This is a major problem which awaits further research. This will be discussed in part two.

Left Image Figure 9 from Lisanti. (1)

Dr Lisanti’s group found that Doxycyline combination therapy for eradication of cancer stem cells worked with other drugs such as the OXPHOS inhibitor, Atovaquone, an anti-malaria drug which inhibits complex III of the mitochondrial electron transport chain.(1)(46) Atavaquone’s chemical structure is similar to CoQ-10, and serves to block activity of Co-Q10 thereby inhibiting respiration in the cancer stem cell.  Atavaquone is already FDA approved for prevention of Pneumocyctis pneumonia in immunosuppressed patients, and easily reaches effective serum levels with routine dosage of 750 mg BID with food.(45-46)

Ignoring the Cancer Stem Cells – the Failure of Oncology

For rapidly proliferating cancer cell types chemotherapy will provide a temporary remission, or reduction in tumor size.  However, cancer stem cells are unaffected by chemotherapy and will induce cancer relapse.  The more aggressive, highly  proliferative cell types relapse within months while the more indolent cell types take longer, and relapse after a few years.  Clearly, targeting cancer stem cells is imperative in order to prevent cancer relapse after treatment.  Unfortunately, current day oncology has failed the cancer patient by ignoring cancer stem cells, and blindly forging ahead with the old chemotherapy protocols, as if medical science is still in the 1960’s, and nothing has changed.

Exemestane – Aromatase Inhibitor for Breast Cancer

Regardless of serum estrogen level which may be quite low in post-menopausal women, many tumors use intracrine estrogen production to stimulate cell growth.  The tumor cells contain upregulated aromatase to produce estrogen locally.  In this scenario, aromatese blocker such as exemestane is beneficial even when serum estrogen is quite low.

Exemestane is a third generation irreversible aromatase inhibitor, and a conventional oncology success story that stands out.(52-53)   In addition to its aromatase blocking activity, exemestane metabolites cause very effective mitochondrial mediated apoptosis of breast cancer cells.(52)  Exemestane also seems effective in lung cancer which frequently expresses estrogen receptors and has aromatase activity (53)(64).   Exemestane may synergize with Doxycycline in treatment of mesothelioma (63)(16).

In-Situ Aromatase Activity in Skin Cancers

Similar to breast cancer cells, skin cells have aromatase activity upregulated in skin cancers to stimulate growth via intratumoral, in-situ, estrogen production (intracrine) independent of serum concentrations which may be quite low in post-menopausal women.  Blocking aromatase activity has been shown effective for skin cancers (65-68)   After all, breast tissue is an appendage of the skin, so estrogen production by the skin via aromatase activity is not unexpected.(65-68)

In- Situ (Intracrine) Aromatase Activity in Colon Cancer

One does not usually associate estrogen production with colonic epithelium or colon cancer cells.  However, Dr Sato in 2012 found this to be the case.(74)  He states:

“All these results demonstrate that colon carcinoma expresses functional aromatase, and that estrogens are locally synthesized in the tumor tissues.”(74)

Synergy of MTOR Inhibition with Exemestane

A number of studies show synergistic cancer cell killing effect when an MTOR inhibitor drug is added to the aromatase inhibitor (exemestane).(69-72)  Note: Itraconazole is a  potent MTOR inhibitor.

Exemestane synergy with simvastatin

Statin drugs such as simvastatin have stand alone anti-cancer activity by activating the intrinsic apoptosis pathway.(76)   In vitro studies show statin drugs induce apoptosis in B Cell Lymphoma. (77)

In a breast cancer cell line study in 2015, Dr Shen studied the synergy of combining exemestane with simvastatin (a common statin drug)  “markedly increased the efficacy, as compared with the single-agent treatment, suggesting that combination treatment could become a highly effective approach for breast cancer.“ (75) Dr Shen says:

“ coadministration of exemestane and simvastatin was shown to result in marked inhibition of tumor cell proliferation, significant cell cycle arrest at G0/G1 phase and induction of apoptosis, as compared with that of the control and individual drug-treated cells.”(75)

More Drug Combinations

A combination of exemestane, doxycycline, itraconazole, fenofibrate, clarithromycin etc might be suggested for the breast cancer patients already on high dose IV vitamin C.  Other Aromatase producing cancer cell types might also benefit from such a combination of drugs which block molecular pathways in cancer cells.

Bone Metastesis on Zolendronic Acid

In those with bone metastasis from breast cancer already on Zoledronic Acid, addition of Doxcycline to the Zoledronic Acid  might be synergistic and more effective.(54-55)

Exemestane and Anti-Cancer Metabolites 

In the drug development for exemestane, researchers may have accidentally stumbled upon a highly effective anti-cancer drug by virtue of the metabolites of exemestane which seem to have a different biological effect inducing “cell cycle arrest and apoptosis via mitochondrial pathway, involving caspase-8 activation”.(61)  Dr Cristina Amaral in 2015 says:

“Our results indicate that metabolites induced, in sensitive breast cancer cells, cell cycle arrest and apoptosis via mitochondrial pathway, involving caspase-8 activation... It was also concluded that….the biological effects of (exemestane) metabolites are different from the ones of exemestane, which suggests that exemestane efficacy in breast cancer treatment may also be dependent on its metabolites.”(61)

More on Doxycycline – Benefits in Ascites and Pleural Effusions

Back in the day when I worked as an interventional radiologist, we commonly removed malignant pleural fluid from breast cancer patients, and then injected doxycycline as a “sclerosing agent”.   In 1994, Dr Wakai discovered that Doxycycline (TCN) suppresses malignant effusions by suppressing tumor growth.(60)  He says:

“it appears that TCNs (Doxycycline) injected into the pleural cavity to manage malignant effusions in man exert their activity, at least in part, by suppressing malignant cell growth.”(60)

Doxycycline as Stand Alone Anti-Cancer Drug

Studies show that doxycycline may be considered effective stand alone anti-cancer therapy.   Doxycycline inhibited a B-cell lymphoma cell line in vitro and in mouse xenograft models (5),  Doxycycline has activity in colon cancer (9), T lymphoblastic leukemia (10) melanoma (11) prostate and breast cancer (12-15), mesothelioma (16) oral squamous cell (17), glioblastoma (18), leukemia (19), Jurkat T lymphocytes (20)  Colorectal cancer cells (21)   Needless to say, doxycycline is more effective when used in combination with drugs that block additional molecular pathways. One of these drugs is the antibiotic, Clarithromycin (Azithromycin) which is synergistic with Doxycycline and Vitamin C  as discussed in my previous article on Clarithromycin.

Conclusion: My hat comes off in admiration and thanks to Michael Lisanti and his group.  This Doxycycline/ Vitamin C combination is a dramatic breakthrough in finding an effective targeted cancer stem cell eradication strategy.  Hopefully, this technique will be incorporated and routinely used on the oncology wards. In the mean time, print out this article and give it to your oncologist.  Ask for and demand the hospital provide Doxycycline and high dose Intravenous vitamin C for your family members undergoing chemotherapy for cancer.

Update 2018:  Latest from Michael Lisanti Lab

Diphenyleneiodonium chloride (DPI), inhibitor of  NADPH/NADH oxidase, and mitochondrial OXPHOS inhibitor was found to be anti-cancer stem cell agent at low concentrations by Michael Lisanti’s Lab.(50) Authors state:

“DPI induced a state of metabolic-quiescence, which potently prevented CSC (cancer stem cell) propagation, selectively depleting cancer stem cell population….DPI, at a concentration of only 10 nM, effectively inhibited OXPHOS and ultimately ATP production, by more than 90% overall. As a consequence, DPI treatment induced a reactive glycolytic phenotype, resulting in the production of high levels of L-lactate….Since DPI targets flavin-containing enzymes, its effects on mitochondrial function may be explained by the pharmacological induction of an acute Riboflavin (Vitamin B2) deficiency.”(50)

DPI is also being considered for anti-mycobacterial therapy, as an Anti-Tuberculosis antibiotic. (51)

This article is part one.  For part two click here.

Articles with related interest:

Clarithromycin and Doxycyclin Combination

Fenofibrate Anticancer Drug

Itraconazole Antifungal and Anticancer Drug

Targeting Cancer Stem cells with Non-Toxic Therapies

Intravenous Vitamin C as Cancer Chemotherapy

Cancer Immune System Evasion with PIBF

Artemisinin Anti-Cancer Drug as Gift from China

Mefloquine Artemisinin Combination

Targeting cancer stem cells with NON-Toxic Therapies

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663

References

1) De Francesco, E. M., Michael Lisanti et al. “Vitamin C and Doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).” Oncotarget (2017). Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).

2) Combining vitamin C with antibiotics destroys cancer stem cells
By Honor Whiteman  published Tuesday 13 June 2017 670

3) Vitamin C and Antibiotic Combo Can Kill Cancer Cells
Posted on June 13, 2017, 6 a.m. in Cancer Immune System Vitamins
Researchers have shown that a combination of antibiotics and Vitamin C can destroy cancer stem cells before they promote the growth of fatal tumors.

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Doxycyline Effective for B Cell Lymphoma

5) Pulvino, Mary, et al. “Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by doxycycline.”
In searching for small-molecule compounds that inhibit proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cells and may, therefore, be exploited as potential therapeutic agents for this disease, we identified the commonly used and well-tolerated antibiotic doxycycline as a strong candidate. Here, we demonstrate that doxycycline inhibits the growth of DLBCL cells both in vitro and in mouse xenograft models. In addition, we show that doxycycline accumulates in DLBCL cells to high concentrations and affects multiple signaling pathways that are crucial for lymphomagenesis. Our data reveal the deneddylating activity of COP-9 signalosome (CSN) as a novel target of doxycycline and suggest that doxycycline may exert its effects in DLBCL cells in part through a CSN5-HSP90 pathway. Consistently, knockdown of CSN5 exhibited similar effects as doxycycline treatment on DLBCL cell survival and HSP90 chaperone function. In addition to DLBCL cells, doxycycline inhibited growth of several other types of non-Hodgkin lymphoma cells in vitro. Together, our results suggest that doxycycline may represent a promising therapeutic agent for DLBCL and other non-Hodgkin lymphomas subtypes.

nice image

6) Barbie, David A., and Brian K. Kennedy. “Doxycycline: new tricks for an old drug.” Oncotarget 6.23 (2015): 19336.

also images
7) Peiris-Pagès, Maria, Federica Sotgia, and Michael P. Lisanti. “Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose.” Oncoscience 2.8 (2015): 696.

8) free pdf
Saikali, Zeina, and Gurmit Singh. “Doxycycline and other tetracyclines in the treatment of bone metastasis.” Anti-cancer drugs 14.10 (2003): 773-778.

9) Onoda, Toshinao, et al. “Tetracycline analogues (doxycycline and COL‐3) induce caspase‐dependent and‐independent apoptosis in human colon cancer cells.” International journal of cancer 118.5 (2006): 1309-1315.

10) Iwasaki, Hiromichi, et al. “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 140.6 (2002): 382-386.

11) Sun, Tao, et al. “Doxycycline inhibits the adhesion and migration of melanoma cells by inhibiting the expression‎ and phosphorylation of focal adhesion kinase (FAK).” Cancer letters 285.2 (2009): 141-150.

12) Lokeshwar, Bal L. “Chemically modified non-antimicrobial tetracyclines are multifunctional drugs against advanced cancers.” Pharmacological research 63.2 (2011): 146-150.

Breast Cancer

13) Zhang, Le, et al. “Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer.” Cell Cycle just-accepted (2016): 00-00.

14) Tang, Xiaoyun, et al. “Doxycycline attenuates breast cancer related inflammation by decreasing plasma lysophosphatidate concentrations and inhibiting NF-κB activation.” Molecular cancer 16.1 (2017): 36.

Doxycycline suppressed both LPA- and TNFα-induced nuclear translocation of NF-κB and blocked the LPA-induced secretion of IL-6, CCL2 and CXCL2 in cancer cells. TNFα-induced nuclear NF-κB transcriptional activity was also inhibited by doxycycline. Under basal condition without stimulation, doxycycline was able to decrease the transcriptional activity of nuclear NF-κB by ~50%

The equivalent dose for human is ~4 mg/kg/day calculated by equivalent surface area dosage conversion factor, which is 240 mg/day for 60 kg of body weight. The typical dose of doxycycline is 100–200 mg/day and the maximum dose is 300 mg/day for more serious infections, such as syphilis.

15) Fife, Rose S., and George W. Sledge Jr. “Effects of doxycycline on in vitro growth, migration, and gelatinase activity of breast carcinoma cells.” The Journal of laboratory and clinical medicine 125.3 (1995): 407-411.

16) Rubins, Jeffrey B., et al. “Inhibition of mesothelioma cell growth in vitro by doxycycline.” Journal of Laboratory and Clinical Medicine 138.2 (2001): 101-106.

17) Shen, Ling-Chang, et al. “Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma–in vitro and in vivo studies.” Oral oncology 46.3 (2010): 178-184.

18) Wang-Gillam, Andrea, et al. “Anti-tumor effect of doxycycline on glioblastoma cells.” Journal of Cancer Molecules 3.5 (2007): 147-153.Anti-Tumor Effect of Doxycycline on Glioblastoma Cells

19) Tolomeo, Manlio, et al. “Effects of chemically modified tetracyclines (CMTs) in sensitive, multidrug resistant and apoptosis resistant leukaemia cell lines.” British journal of pharmacology 133.2 (2001): 306-314.

20) Liu, Jian, Charles A. Kuszynski, and B. Timothy Baxter. “Doxycycline induces Fas/Fas ligand-mediated apoptosis in Jurkat T lymphocytes.” Biochemical and biophysical research communications 260.2 (1999): 562-567.

21) Onoda, Toshinao, et al. “Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells.” Journal of Laboratory and Clinical Medicine 143.4 (2004): 207-216.

22) Fife, Rose S., et al. “Effects of tetracyclines on angiogenesis in vitro.” Cancer letters 153.1 (2000): 75-78.

23) Sagar, Jayesh, et al. “Doxycycline in mitochondrial mediated pathway of apoptosis: a systematic review.” Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 10.7 (2010): 556-563.

24) Richards, Christopher, Liron Pantanowitz, and Bruce J. Dezube. “Antimicrobial and non-antimicrobial tetracyclines in human cancer trials.” Pharmacological research 63.2 (2011): 151-156.

25) van den Bogert, Coby, et al. “Arrest of the proliferation of renal and prostate carcinomas of human origin by inhibition of mitochondrial protein synthesis.” Cancer research 46.7 (1986): 3283-3289.

26) Kroon, Albert M., et al. “The mitochondrial genetic system as a target for chemotherapy: tetracyclines as cytostatics.” Cancer letters 25.1 (1984): 33-40.

27) van den Bogert, Coby, Bert HJ Dontje, and Albert M. Kroon. “The antitumour effect of doxycycline on a T-cell leukaemia in the rat.” Leukemia research 9.5 (1985): 617-623.

Antibiotics Eradicate Cancer Stem Cells

2015 OncoTarget

28) Lamb, Rebecca, et al. “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease.”  Lamb Rebecca Antibiotics that target mitochondria effectively eradicate cancer stem cells 2015 OncoTarget  Lamb Rebecca Antibiotics that target mitochondria effectively eradicate cancer stem cells 2015 OncoTarget

Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

Doxycycline for Lymphoma

2015
29) Ann Hematol. 2015 Apr;94(4):575-81. Long-term outcomes of first-line treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell lymphoma. .  Han JJ1, Kim TM, Jeon YK, Kim MK, Khwarg SI, Kim CW, Kim IH, Heo DS.
Author information 1Department of Internal Medicine, Seoul National University Hospital, 101  Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.

Ocular adnexal lymphoma (OAL) has been associated with Chlamydophila psittaci infection, for which  doxycycline has been suggested as a treatment option. We conducted this study to eval‎uate the long-term results of first-line doxycycline treatment in patients with OAL. Ninety patients withhistologically confirmed OAL with marginal zone B cell lymphoma were enrolled. Each patient received one or two cycles of doxycycline (100 mg bid) for 3 weeks. After a median follow-up period of 40.5 months (8-85), the 5-year progression-free survival (PFS) rate was 60.9 %. All patients were alive at the last follow-up date. Thirty-one patients (34 %) showed local treatment failure without systemic spread. However, PFS rate in these patients was 100 % after salvage chemotherapy and/or radiotherapy.

PFS was independently predicted in multivariate analysis by the tumor-node-metastasis (TNM) staging (hazard ratio [HR], 4.35; 95 % confidence interval [CI], 2.03-9.32; P < 0.001) and number of cycles of doxycycline (HR, 0.31; 95 % CI, 0.14-0.69; P = 0.004). No serious adverse event was reported during doxycycline therapy. In conclusion, first-line doxycycline therapy was effective and safe.

Patients who failed to respond to doxycycline therapy were successfully salvaged with chemotherapy and/or radiotherapy without compromising long-term outcomes. Patients with T1N0M0 disease could be considered good candidates for first-line doxycycline.

2015

13 patients antibiotics alone for gastric lymphoma – HP eradication regimen

30) Ann Hematol. 2015 Jun;94(6):969-73. doi: 10.1007/s00277-014-2298-3. Epub 2015 Jan 13. Antibiotic treatment as sole management of Helicobacter pylori-negative gastric MALT lymphoma: a single center experience with prolonged follow-up.  Raderer M1, Wöhrer S, Kiesewetter B, Dolak W, Lagler H, Wotherspoon A, Muellauer L, Chott A.

Relatively little is known about the long-term outcome of patients with Helicobacter pylori (HP)-negative gastric lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with antibiotic therapy as sole management. We have analyzed all patients with HP-negative gastric MALT lymphoma undergoing antibiotic therapy as sole management of their disease. HP negativity was defined as negative histology, breath test and serology, and response to treatment, survival and long-term outcome was assessed together with clinico-pathological characteristics including t(11; 18) (q21; q21) translocation. Out of 97 patients with gastric MALT lymphoma, 24 were HP-negative, and 13 (5 females and 8 males) underwent only antibiotic management for initial therapy. Eight had stage I and five were found to have stage II disease, with three patients suffering from an underlying autoimmune disease. Antibiotic therapy consisted of standard HP eradication regimens consisting of clarithromycin in all patients, along with metronidazole in seven and amoxicillin in six plus a proton-pump inhibitor. After a median follow-up of 95 months (42-, 181+), 12/13 patients are alive. Six patients with stage I disease achieved an objective response (five complete (CR) and one partial remission, 46 %), four had stable disease (lasting 11-27 months), and three progressed. All patients with stable disease received chemotherapy, but only one patient due to clear cut progression. One patient relapsed 23 months after initial CR, and achieved a second CR with antibiotics now lasting 87 months. These results indicate that a relevant percentage of patients with HP-negative gastric MALT lymphoma may benefit from antibiotic therapy and do not require additional oncological therapies. Our data suggest that the remissions seen in these patients might be durable as evidenced by prolonged follow-up in our series.

2013

31) Kiesewetter, Barbara, and Markus Raderer. “Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature” Blood 122.8 (2013): 1350-1357.

A single course of oral doxycycline at a dose of 100 mg given twice a day for 3 weeks was the most popular regimen and was used by most investigators.14⇓⇓-17,19⇓⇓-22 By contrast, Kim and coworkers19 added a second course after an interval of 3 weeks for patients with residual eye-related symptoms after the initial cycle. The activity of a 6-month oral application of 500 mg clarithromycin twice a day was assessed in an Italian pilot study,18 assuming potential additional direct anticancer effects of macrolide antibiotics through changes in apoptotic mechanisms of tumor cells. In addition, 1 patient received HP eradication as first-line treatment of OAML.  CR was achieved in 23 patients (18%) out of the collective of all 131 patients reported. Thirty-six (27%) had a PR

2006

32) Ferreri, Andrés JM, et al. “Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial.” Journal of the National Cancer Institute 98.19 (2006):1375-1382.

Background: An association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infection has been proposed, and recent reports suggest that doxycycline treatment causes tumor regression in patients with Cp-related OAL. The effectiveness of doxycycline treatment in Cp-negative OAL has not been tested. Methods: In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were two-sided. Results: Eleven patients were Cp DNA–positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in six patients, and a partial response (≥50% reduction of all measurable lesions) was observed in seven patients (overall response rate [complete and partial responses] = 48%). Lymphoma regression  was observed in both Cp DNA–positive patients (seven of 11 experienced regression) and Cp DNA–negative patients (six of 16 experienced regression) (64% versus 38%; P = .25, Fisher’s exact test). The three patients with regional lymphadenopathies and three of the five patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline- treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. Conclusions: Doxycycline is a fast, safe, and active therapy for Cp DNA–positive OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR-negative OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria.

Ferreri et al conducted a prospective phase 2 clinical trial of 27 patients (15 newly diagnosed and 12 relapsed) with OAML, using doxycycline 100 mg orally twice daily for 3 weeks.  Partial or complete lymphoma regression after antibiotic therapy was observed in 7 of 11 Cp-positive and 6 of 16 Cp-negative patients, with an overall response rate of 48%. The 2-year failure-free survival rate among patients treated with doxycycline was 66%

Abramson et al84 treated 3 patients with biopsy-proven conjunctival MALT lymphoma with antibiotic therapy, resulting in 2 complete remissions and 1 partial response.

Husain et al43 conducted a meta-analysis, identifying 4 studies with a total of 42 patients who had  been treated with oral doxycycline.

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