Der Extrakt aus dem Prostatakrebs-Forum von KISP und BPS

Medikamente – Antibiotika

Richard fragte am 4.4.2002 verzweifelt:

Hallo Freunde,

PSA über 300, intervalartige Knochenschmerzen, oft Nachts, manchmal am Tage. Jetzt werden (wenn) nur noch Experimente durchgeführt. Habe gehört, dass Holtransferrin auch andere Stofffe als Artemisinin in die Zellen befördert. Insbesondere Anitbiotika. Ich suche nun nach einen Antibiotikum, welches gegen Krebszellen wirkt, um das mit Holotransferrin zielgerichtet (targeting cancer cells) einzusetzen. Wenn jemand ein solches Antibiotikum kennt, bitte ich um Eure Antwort.

Peter reagierte am selben Tag:

Ich hab das folgende gefunden (ich kann's natürlich nicht bewerten):

A recent randomized trial compared the steroid, prednisone, with the combination of prednisone and the cytotoxic antibiotic mitoxantrone, in patients with hormone-refractory prostate cancer. There was no difference in survival between the two groups, but the combined therapy group had better quality-of-life scores. A decrease in PSA levels of over 50 % was reported in 22 % of patients who received only prednisone [79].

[79] Tannock I, Osoba D, Stockler MR et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14: 1756-64.
http://www.sos.se/mars/sta026/sta26app.pdf target="new"

Und Wil schrieb, ebenfalls am selben Tag:

In Mäusen wurde festgestellt, dass Tetracyclin (ein angeblich bekanntes Antibiotikum) Metastasen von PK in den Knochen mit 70 % zurückdrängt. Die angewendete Dosis soll relativ niedrig sein, weniger als bei der normale Anwendung (gegen "Akne"?).

Mit Google auf http://www.google.com/ habe ich die folgende Wörter eingegeben: doxycycline cancer MMP bone prostate CMT-3. Dann kommt nichts.

Interessant ist auch http://www.moffitt.usf.edu/pubs/ccj/v6n5/article3.htm Review of Three New Agents That Target Angiogenesis, Matrix Metalloproteinases, and Cyclin-Dependent Kinases.

Habe vorgestern auch gesucht, nochdem du nach Antibiotika gefragt hattest. Es geht darum, MMP zu unterdrücken. Das geht mit Tetracyclin. Tetracycline sind eine Familie von Antibiotica. Doxycycline gehört zu dieser Familie.

Ich schicke dies erst mal ab, denn es kostet viel mehr Zeit, die beste Informationen über diese Therapie zu finden. Wer kann suchen helfen?

Cheap, Common Acne Medicine Might Hold Cure to Cancers, Researchers Say Canadian Press, March 28, 2002.

HAMILTON (CP) - Researchers at the Hamilton Regional Cancer Centre have found that a common acne medication can reduce certain kinds of cancer tumours by a staggering 70 per cent in animal tests.

The discovery may one day lead to a safe and inexpensive cancer treatment that could spare the lives of thousands of Canadians who die each year after their breast or prostate cancer spreads to the bones.

Dr. Gurmit Singh, director of research at the cancer centre and the lead investigator of the project, expects clinical trials to begin this summer.

"I am thrilled with the results," said Singh. "I'd just like to get it into the clinic. It's only great news once it's tested in people. A lot of people have cured a lot of mouse tumours in the past."

Breast and prostate cancer are two of the most common forms of the disease, making up more than a quarter of all new cases that are diagnosed in Canada.

One of cancer's most lethal characteristics is that cancerous cells can slip away from the original tumour and migrate through the body to other locations.

These new tumours - called metastases - can take root in other organs and it's often these secondary tumours that cause death.

For reasons still not fully understood, breast and prostate cancer metastases prefer to migrate into bones. Between 70 to 80 per cent of breast cancer metastases and up to 70 per cent of prostate cancer metastases end up in bones.

Singh and his team discovered that tetracycline - an effective, dollar-a-day antibiotic that has been around for decades - can attack tumours that have migrated to bones.

Using mice that were genetically programmed to develop metastatic human breast and prostate cancer tumours, the researchers found that tetracycline reduced the total tumour volume by 70 per cent in the animals.

"That's an amazing finding," said Dr. Stuart Edmonds, assistant director of research programs at the National Cancer Institute of Canada.

"To have a significant finding like this is an important starting point."

Tumour cells in the bone pump out an enzyme called matrix metalloproteinase, which chews up the bone and allows the tumour to expand.

Tetracycline gets absorbed by the bones, however, and blocks the enzyme from breaking down bone tissue.

More importantly, the Hamilton researchers also found that tetracycline can kill the metastatic tumour cells.

"There's a very old hypothesis called Paget's hypothesis that says if the soil is rich, the seed will grow," Singh explained.

"Bone is fertile ground for certain kinds of cancers."

Tetracycline doesn't stop the signalling process that attracts bone metastases but it does make the bone inhospitable once the tumour cells get there.

"The soil isn't as fertile," said Singh. "It will kill them."

But Singh's group also stumbled upon an unexpected bonus.

They discovered that tetracycline not only killed tumour cells and stopped bone loss, it also promoted the growth of new bone tissue.

That's significant because broken bones are a common problem for cancer patients with bone metastases.

Just over half of all women with metastatic breast cancer will suffer a bone fracture.

"The cost savings would be huge in terms of hospitalization and also the quality of life of these patients," Singh added.

The researchers hope to start clinical trials on prostate cancer patients in July or August, and then begin a second trial with breast cancer patients.

"We don't know what we'll find in humans," cautioned Singh. "Even if we got a 20 per cent response in our clinical trials, we're looking at a big change."

(Hamilton Spectator)

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Cancer Res 2002 Mar 15;62(6):1588-91

Doxycycline decreases tumor burden in a bone metastasis model of human breast cancer.

Duivenvoorden WC, Popovic SV, Lhotak S, Seidlitz E, Hirte HW, Tozer RG, Singh G.

Hamilton Regional Cancer Centre and McMaster University, Hamilton, Ontario, L8V 5C2 Canada.

Bone is one of the most frequent sites for metastasis in breast cancer patients,often resulting in significant clinical morbidity and mortality. Increased matrix metalloproteinase (MMP) activity of tumor cells correlates with a higher invasive and metastatic potential. Members of the tetracycline family of antibiotics, including doxycycline, have potential treatment value for bone metastasis; they inhibit cancer cell proliferation, and they are also potent MMP inhibitors and are highly osteotropic. Doxycycline treatment in an experimental bone metastasis mouse model of human breast cancer MDA-MB-231 cells resulted in a 70% reduction in total tumor burden when compared with placebo control animals. In tumor-bearing animals, the amount of doxycycline incorporated into the radius/ulna as assessed by ELISA was lower than in non-tumor-bearing animals. In doxycycline-treated mice, bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface, and volume, whereas a decrease in bone resorption was also observed. Doxycycline treatment may be beneficial for breast cancer patients with or at risk for osteolytic bone metastasis; it greatly reduces tumor burden and could also compensate for the increased bone resorption associated with the disease.

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http://www.bentham.org/cmcaca1-1/papavasil/papavassilioums.htm

Both angiogenesis and tumor invasion require controlled degradation of the extracellular matrix (ECM) components to allow cell migration and tissue formation. Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases, that play a significant role during the development and metastasis of prostate cancer, as the malignant prostate cells secrete high levels of MMPs and low levels of endogenous MMP inhibitors (TIMPs), resulting in an excess balance of MMPs. Furthermore, established prostate cancer cell lines that express high levels of MMPs frequently metastasize to bone and lungs [150]. Several studies have shown an association of increased production of MMP-2, -3, -7 and -9 with decreased levels of their inhibitors, during malignant progression of prostate cancer [151,152]. For instance, the levels of both MMP-2 and MMP-9 were found to be low in normal prostate and organ-confined tumors with a Gleason sum 5 or lower, whereas they were highly expressed in high Gleason sum (8-10) prostate tissues [153]. Owing to the large body of evidence suggesting the implication of MMPs in prostate cancer promotion and metastasis, inhibition of MMP activity may be an attractive route to treat advanced prostate cancer.

The strategy of using the superinduction of TIMPs to control metastasis, although exciting, is not very practical at present because TIMPs are large glycoproteins and require a significant portion of the molecule for biological activity. To overcome this limitation, smaller synthetic MMP inhibitors have been developed such as BB-94 (batimastat) and BB2516 (marimastat), whose hydroxamate group reversibly chelates the zinc atom at the active site of MMPs (reviewed in [154]). Clinical studies using these two oral MMP inhibitors in advanced disease, demonstrated a dose-dependent response, as measured by decrease in the rate of rise of PSA [155,156]. Moreover, AG3340 (prinomastar) is a novel selective MMP inhibitor, currently in phase III clinical trials in combination with mitoxantrone for the treatment of advanced prostate cancer [157]. Noteworthy, among other oral nontoxic synthetic MMP inhibitors tested, such as doxycycline and chemically-modified tetracyclines (CMT), the CMT-3 (6-deoxy, 6-dimethyl, 4-de-dimethylamino tetracycline) showed highest activity against prostate cancer cell proliferation and invasion, inhibiting skeletal metastases [158].

Referenz:

[158] Lokeshwar, B.L. and Ann. N.Y. Acad. Sci., 1999, 878, 271-289.

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http://www.bentham.org/cmc/cmc8-3.htm

CMT-3, a Non-antimicrobial Tetracycline (TC), inhibits MT1-MMP Activity: Relevance to Cancer.

Lee H.M., Golub L.M., Cao J., Teronen O., Laitinen M., Salo T., Zucker S. and Sorsa T.

Tetracyclines (TCs) and their non-antimicrobial analogs (CMTs) have therapeutic potential to inhibit tissue destructive disease processes, such as cancer invasion and metastasis, by inhibiting certain matrix metalloproteinases. Enhanced matrix metalloproteinase-2 (MMP-2; gelatinase A) activity has been correlated to cancer invasiveness, and membrane type MMP (MT1-MMP) expressed by tumor cells is involved in localizing and activating pro-MMP-2, a pathway believed to mediate cancer induced tissue breakdown. CMT-3 (6-demethyl, 6-deoxy, 4-dedimethylamino TC) has been shown to experimentally suppress prostate cancer, colon adenocarcinoma and melanoma invasiveness in cell culture and to inhibit tumor growth and metastasis in vivo and was used in the current in vitro study. Confluent MT1-MMP transfected COS-1 cells were harvested, washed thoroughly, subjected to N 2 cavitation and cell membrane enriched fractions were isolated by sequential centrifugations. This MT1-MMP preparation exhibited
(i) pro-MMP-2 activating activity as shown by molecular weight shift of this gelatinase from 72 kDa to 62 kDa using gelatin zymography, and
(ii) the ability to degrade both [ 3 H-methyl] gelatin and casein at 37 o C.
Adding CMT-3 at final concentrations of 5 - 20 mM inhibited MT1-MMP gelatinolytic and caseinolytic activity, blocked MT1-MMP activation of pro-MMP-2, and decreased invasiveness (using the Matrigel system) of HT-1080 fibrosarcoma cells. The inhibition of MT1-MMP by CMT-3 may partially explain the inhibition of cancer cell-mediated tissue breakdown and invasiveness by this non-antimicrobial tetracycline analog.

Guy trug mit dem folgenden Fund zu Richards Nachfrage bei:

Ein wirksames Antibiotikum ist mir nicht bekannt. Ich habe aber gemerkt, dass mittlerweile ein Malariamedikament mit dem Namen Riamet (Novartis) zugelassen ist. Es ist ein Kombinationspräparat aus Artemether, einem Artesemin-Derivat aus der traditionellen chinesischen Pflanzenheilkunde, und dem synthetischen Wirkstoff Lumefantrin. Es wurde in Zusammenarbeit mit chinesischen Wissenschaftlern entwickelt. Riamet soll auch von Kindern gut vertragen werden.

Seit dem Juli 2001 ist Riamet (Artemether/Lumefantrin) auch in Deutschland zur Behandlung (Stand-by) einer unkomplizierten Malaria topica bei Erwachsenen und Kindern ab 12 Jahren zugelassen worden. Ein Behandlungszyklus umfasst 6 Dosen mit je 4 Tabletten innerhalb eines Zeitraums von 60 Stunden, und zwar nach der Anfangdosis im Abstand von 8, 24, 36, 48 und 60 Stunden. http://www.loewen-apotheke.de/Pages/S_Gesund/l_prtexte.html

Das Medikament (Riamet) müsste wohl schneller und besser wirken als das Naturprodukt (Artemisin). Vielleicht kannst du den behandelnden Arzt diesbezüglich befragen.

Peter meldete sich am 5.4.2002 mit dem folgenden Vorschlag:

in Pubmed findet man unter "prostate cancer antibiotics" 691 Kurzberichte. Wenn Du die Suche mit weiteren Begriffen verdichtest, wird es übersichtlicher.

[Richard ("Ritschi") verstarb am 14.7.2002 an seinem hormonrefraktären Prostatakrebs, der u. a. in die Knochen und die Leber metastasiert hatte. - Ed]