benefits of giving zoledronic acid after doxorubicin [Archive]

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Rich66

09-04-2008, 04:43 PM

Cheap drug hope for breast cancer
A combination of two inexpensive existing drugs may offer a new way to treat breast cancer, according to UK and Finnish researchers.
The common chemotherapy drug and a brittle bone medicine almost completely stopped the growth of tumours in mice.
The Journal of the National Cancer Institute said the combination cost a twentieth of Herceptin, given to breast cancer patients by the NHS.
Specialists said the results of human trials now under way would be crucial.

<table> <tbody><tr> <td width="5">
</td> <td class="fact">  The results of this study could change the way breast cancer patients are treated
  Pamela Goldberg
Breast Cancer Campaign  </td> </tr> </tbody></table>
In the UK, almost 46,000 new cases of breast cancer are diagnosed each year.
Although modern treatments mean that cases caught sufficiently early, some via breast screening programmes, have an excellent chance of being successfully treated.
The study was a joint project between researchers at the University of Sheffield and the Kuopio University in Finland.
Its findings could offer an even more effective way to help some patients.
It used a dose of the drug doxorubicin, a common component of chemotherapy regimes, followed 24 hours later by zoledronic acid, currently given to osteoporosis patients.
In the mice, this stopped 99.99% of new cancer cell growth in tumours.
It is thought the first drug could be "priming" the tumour to be more sensitive to the cancer-cell killing qualities of the second drug.
Dr Ingunn Holen, who led the study, said that the study showed that the drug cocktail could "kill breast tumours".
"These results show that a patient may benefit the most if these two drugs are given in this particular order."
She said that the results of a human trial were expected later this year.
Speed advantage
If that proves successful, the drugs would not have to undergo a lengthy licensing process, simply have the change of use included in their current licence.
Breast Cancer Campaign, the charity which funded the study, said it was encouraged by the potential for the drug to be made swiftly available to women.
Its chief executive, Pamela Goldberg, said: "The results of this study could change the way breast cancer patients are treated.
"The good news is the that the two treatments are relatively inexpensive and already used in the clinic."
A spokesman for Cancer Research UK said that a study in humans would be important.
"Establishing the most effective combinations of drug treatments and the timings in which they are given is an important area of clinical research.
"But the benefits of giving zoledronic acid after doxorubicin have only been shown here in mice and now need to be evaluated more fully in people with breast cancer."

Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/7558327.stm

Published: 2008/08/13 10:25:34 GMT

© BBC MMVIII

And the pubmed abstract:

<dl class="AbstractPlusReport"><dt class="head">J Natl Cancer Inst. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27J%20Natl%20 Cancer%20Inst.%27%29;) 2008 Aug 20;100(16):1167-78. Epub 2008 Aug 11.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-custom-oxfordjournals_final.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=18695136&db=pubmed&url=http://jnci.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=18695136) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu18695136%29;)
</dt><dd class="abstract"> Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer.

Ottewell PD (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ottewell%20PD%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mönkkönen H (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22M%C3%B6nkk%C3%B6nen%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Jones M (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Jones%20M%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lefley DV (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Lefley%20DV%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Coleman RE (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Coleman%20RE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Holen I (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Holen%20I%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Academic Unit of Clinical Oncology, School of Medicine and Biomedical Sciences, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. i.holen@sheffield.ac.uk.
BACKGROUND: The potent antiresorptive drug zoledronic acid (Zol) enhances the antitumor effects of chemotherapy agents in vitro. We investigated the effects of clinically achievable doses of doxorubicin (Dox) and Zol, given alone, in sequence, and in combination, on the growth of established breast tumors in vivo. METHODS: Female MF1 nude mice were inoculated subcutaneously with 5 x 10(5) human breast cancer MDA-MB-436 cells that stably expressed green fluorescent protein (ie, MDA-G8 cells). Beginning on day 7 after tumor cell injection, the mice were injected weekly for 6 weeks with saline, Dox (2 mg/kg body weight via intravenous injection), Zol (100 microg/kg body weight via intraperitoneal injection), Dox plus Zol, Zol followed 24 hours later by Dox, or Dox followed 24 hours later by Zol (n = 8-9 mice per group). The effects of treatment on tumor growth were determined by measuring tumor volume; on tumor cell apoptosis and proliferation by immunohistochemistry using antibodies for caspase-3 and Ki-67, respectively; and on bone by microcomputed tomography and bone histomorphometry. All P values are two-sided. RESULTS: Treatment with Dox or Zol alone or Zol followed 24 hours later by Dox did not statistically significantly decrease final tumor volume compared with saline. Mice treated with Dox plus Zol had statistically significantly smaller final tumor volumes than those treated with Dox alone (mean = 122 mm(3) vs 328 mm(3), difference = 206 mm(3), 95% confidence interval [CI] = 78 to 335 mm(3), P < .001), with Zol alone (122 mm(3) vs 447 mm(3), difference = 325 mm(3), 95% CI = 197 to 454 mm(3), P < .001), or with Zol followed 24 hours later by Dox (122 mm(3) vs 418 mm(3), difference = 296 mm(3), 95% CI = 168 to 426 mm(3), P < .001). Treatment with Dox followed 24 hours later by Zol almost completely abolished tumor growth. Tumors from mice that were treated with Dox followed by Zol had more caspase-3-positive cells than tumors from mice treated with saline (mean number of caspase-3-positive cells per square millimeter: 605.0 vs 82.19, difference = 522.8, 95% CI = 488.2 to 557.4, P < .001), with Zol alone (605.0 vs 98.44, difference = 506.6, 95% CI = 472.0 to 541.2, P < .001), or with Zol followed by Dox (605.0 vs 103.1, difference = 501.9, 95% CI = 467.3 to 536.5, P < .001). The treatment-induced increase in the number of caspase-3-positive cells was mirrored by a decrease in the number of tumor cells positive for the proliferation marker Ki-67. No evidence of bone disease was detected in any of the treatment groups following microcomputed tomography and histological analysis of bone. CONCLUSION: Sequential treatment with Dox followed by Zol elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease.</dd></dl>
http://jnci.oxfordjournals.org/cgi/content/abstract/100/16/1167
Results: Treatment with Dox or Zol alone or Zol followed 24 hours later by Dox did not statistically significantly decrease final tumor volume compared with saline. Mice treated with Dox plus Zol had statistically significantly smaller final tumor volumes than those treated with Dox alone (mean = 122 mm3 vs 328 mm3, difference = 206 mm3, 95% confidence interval [CI] = 78 to 335 mm3, P < .001), with Zol alone (122 mm3 vs 447 mm3, difference = 325 mm3, 95% CI = 197 to 454 mm3, P < .001), or with Zol followed 24 hours later by Dox (122 mm3 vs 418 mm3, difference = 296 mm3, 95% CI = 168 to 426 mm3, P < .001). Treatment with Dox followed 24 hours later by Zol almost completely abolished tumor growth. Tumors from mice that were treated with Dox followed by Zol had more caspase-3–positive cells than tumors from mice treated with saline (mean number of caspase-3–positive cells per square millimeter: 605.0 vs 82.19, difference = 522.8, 95% CI = 488.2 to 557.4, P < .001), with Zol alone (605.0 vs 98.44, difference = 506.6, 95% CI = 472.0 to 541.2, P < .001), or with Zol followed by Dox (605.0 vs 103.1, difference = 501.9, 95% CI = 467.3 to 536.5, P < .001). The treatment-induced increase in the number of caspase-3–positive cells was mirrored by a decrease in the number of tumor cells positive for the proliferation marker Ki-67. No evidence of bone disease was detected in any of the treatment groups following microcomputed tomography and histological analysis of bone. 
Conclusion: Sequential treatment with Dox followed by Zol elicited substantial antitumor effects in subcutaneous breast tumors in vivo, in the absence of bone disease. 

<hr size="2">
<table border="1" cellpadding="10"><tbody><tr bgcolor="#e1e1e1"><td>CONTEXT AND CAVEATS Prior knowledge
Zoledronic acid is a potent inhibitor of osteoclastic bone resorption that also enhances the antitumor effects of chemotherapy agents both in vitro and in in vivo models with a high degree of tumor-induced bone disease.
Study design
An examination of the effects of clinically achievable doses of doxorubicin and zoledronic acid, given alone, in sequence, and in combination, on the growth of tumors derived from a human breast cell line that does not metastasize readily to bone in a mouse model.
Contribution
Sequential treatment with doxorubicin followed by zoledronic acid inhibited the growth of subcutaneous breast tumors in vivo, in the absence of bone disease.
Implications
There may be benefits of combining zoledronic acid with cytotoxic agents for the treatment of patients with early-stage breast cancer.
Limitations
Mice were treated with higher total doses of the drugs than those that breast cancer patients receive. The relevance of the mouse model to humans is not certain.
From the Editors

</td></tr></tbody></table>
Manuscript received December 17, 2008; revised June 2, 2008; accepted June 16, 2008.

Lani

09-11-2008, 03:55 AM

Not only might they not reflect the behavior of breast cancer in its own milieu(the human patient with the special changes present in the tissues which surround the cancer and their circulating and local hormonal, immune and other substances) and due to changes in the cell lines caused by the many years they have adapted to non-physiologic surroundings (growing on strange materials in petri dishes with strange "cocktails" of substances found to be required for perpetuating them in such a strange environment, let alone changes caused by implantation in a foreign species (even those bred to have deficient immune systems), but also because few readers of articles bother to check the characteristics of the cell lines discussed--and breast cancer is not one disease but a mixture of many, like an exotic fruit salad, you can't compare apples with oranges with kiwis, guavas or passionfruits.

Here is a source of some cell lines discussed according to their ER and her2 status. I believe I may have cited an even better list about three years ago (search function may help)

http://www.geocities.com/m.lacroix/bcrt4.htm

This paper presents MDA MB-436 as an ER- her2- breast cancer cell line, hence the dangers inherent in interpreting the Zoledronic acid,anthracycline
combination papers as applicable for her2+ breast cancers, whether ER+ like your mother's or ER-

Rich66

09-12-2008, 07:15 PM

One of the researchers involved tells me:

the survival benefit for the mice was substantial. As a
consequence of having low tumour burden the mice in the group receiving
sequential treatment with doxorubicin followed by zoledronic acid all survived
for many months longer than the animals receiving single treatments. The
precise survival data are currently being submitted for publication so you
should be able to read more in a few months.

As for the trials in patients we can not release the results from this until the
study is complete and the data analysed in a blinded fashion by an independent
data monitoring committee. This to avoid any chance of researcher bias and
spreading of the wrong information. We are expecting this work to be in the
public domain towards the end of the year.

I have read that this trial is a neoadjuvant setting. Maybe there are others.

Rich66

12-13-2008, 04:18 PM

<dl class="AbstractPlusReport"><dt class="head">This seems encouraging to me in that those who have failed anthracyclines or who can't rsik cardiac toxicity might have benefit of Zolendronate sequencing:
</dt><dt class="head">
</dt><dt class="head">
</dt><dt class="head">: Tumour Biol. (http://javascript%3Cb%3E%3C/b%3E:AL_get%28this,%20%27jour%27,%20%27Tumour%20Bi ol.%27%29;) 2006;27(2):92-103. Epub 2006 Mar 24.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.karger.com-images-sk_nlm_ft.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3030&itool=AbstractPlus-def&uid=16582586&db=pubmed&url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=TBI2006027002092) <script language="JavaScript1.2"></script>Links (http://javascript%3Cb%3E%3C/b%3E:PopUpMenu2_Set%28Menu16582586%29;)
</dt><dd class="abstract"> Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro.

Neville-Webbe HL (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Neville-Webbe%20HL%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Evans CA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Evans%20CA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Coleman RE (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Coleman%20RE%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Holen I (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Holen%20I%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Cancer Research Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, UK.
Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment. The synergistic interaction persists at clinically relevant concentrations and incubation periods. We report that the sequential treatment is associated with cell cycle changes and depends on breast cancer cell characteristics, with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis. Finally, we have found that the synergistic induction of apoptosis is via zoledronic acid-mediated inhibition of the mevalonate pathway.
</dd></dl>