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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Getting Drug Research Really, Really Wrong | Main | Donald Light Responds on Drug Innovation and Costs »

August 10, 2012

Making Tumor Cells More Vigorous Through. . .Chemotherapy?

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Posted by Derek

Here's some food for thought: in some cases, chemotherapy may actually accelerate the growth of tumor cells. This study has found that noncancerous cells (which are also affected, to various degrees, by most chemotherapy agents) can secrete Wnt16B in response to treatment, and that this protein is taken up by nearby tumor cells.

And that's not good. Here's the full paper, which looks at prostate cells. The secretion of the Wnt protein is mediated by NF-kappa-B in response to the DNA damage caused by many therapeutic agents, and it acts as a paracrine signal for the surrounding cells. And the resulting initiation of the Wnt pathway is bad news, because that's already been implicated in tumor cell biology. Here's the bad news slide: conditioned media from cultures of the normal prostate fibroblast cells, after exposure to therapeutic agents, causes prostate tumor cells to proliferate and become more mobile, an effect that can be canceled out by blocking Wnt16b.

Finding out that this can be set off by normal cells in the neighborhood means that we may need to do some rethinking about how chemotherapy is administered. But it would also seem to open a window to block Wnt signaling as an adjunct therapy. That's already been the subject of a good amount of research, since the importance to tumor biology was already known - here's a recent review. Development of these agents now looks more useful than ever. . .

Comments (19) + TrackBacks (0) | Category: Cancer


COMMENTS

1. MDACC Student on August 10, 2012 8:54 AM writes...

I've always assumed this, taking hints from wound models. And in general it's logical to me that if a cell is wounded, it would signal to it's brothers that it needs help. Unfortunately my inst. takes the approach postdoc=technician so there isn't much room to explore new concepts.

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2. Helical_Investor on August 10, 2012 10:08 AM writes...

Moving ever closer to a cocktail approach to oncology treatment.

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3. rtw on August 10, 2012 10:14 AM writes...

One should have a look at a TED talk I saw not long ago on the internet given by Mina Bissell. She pursued a revolutionaly idea that cancer cells become tumors because of their surrounding micro environment. This result certainly points to that.

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4. Carl Lumma on August 10, 2012 12:10 PM writes...

Know what tumor cells can't pull a stunt like this with? Alpha particles.

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5. SirMixAlot on August 10, 2012 1:14 PM writes...

Reading the comments from the original article... there is a debate - chemo vs. natural means to treat cancer. Articles like this tend to confuse the public into thinking chemo actually kills you and you have a better chance of living with natural treatments.
This is complete and utter BS. Data doesnt lie, people. Chemotherapy SAVES LIVES! Unfortunately, the real problem is how complicated cancer can be and how specialized treatments can become upon learning more about the specific type of cancer. Take breast cancer... there are many different treatment plans/drug cocktails depending on the presence/lack of certain receptors, genetic considerations, etc. Breast cancer is arguably the most studied form of cancer out there, and as a result is becoming the most diversely chemo-treated forms of cancer.
Moral of the story... we know very little about cancer to suggest all treatments are deleterious/successful based on globally defined "chemotherapy." Based on the data, approved chemotherapy treatments prolong life in a statistically significant population. Whether or not each patient will be on the good side of the bell curve or not is based on unknown factors. If I had a choice between dying and possibly being on the good side of the curve, Im getting chemo... period.

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6. Rev. Howard Furst on August 10, 2012 3:59 PM writes...

rtw: "cancer cells become tumors because of their surrounding micro environment"

The blasted things also actively manipulate their local environment and even send out molecular emissaries to distant sites to make them more hospitable to subsequent implantation of circulating metastatic cells.

http://www.nature.com/nrc/journal/v8/n11/full/nrc2525.html

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7. rtw on August 10, 2012 8:19 PM writes...

@6

No doubt. It is a complex system, and every little increment we can eck out in our understanding helps. I spent the majority of 20 years in pharma attempting to find less toxic ways to kill the buggers. When I began, almost all drugs we worked on were toxic to normal cells. DNA Binders, Topo inhibitors, radiosensitizers, Platinum complexes, this list goes on. Gradually moved into antiangiogenesis, and other Kinase inhibitors as more targeted drugs. Success is fleeting at best.

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8. eugene on August 10, 2012 8:48 PM writes...

"Know what tumor cells can't pull a stunt like this with? Alpha particles."

Do Alpha particles cause less DNA damage, or are they administered more selectively? I think it has to be a localized effect thing. I assume alpha particles are produced by an emitter which also gives off the radiation which kills the cancer cell. If you shoot gamma rays at healthy cells, I can't imagine why they wouldn't also release Wnt16B. Unless the normal cell is also killed after a few hits before it realizes what happened.

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9. gippgig on August 10, 2012 10:22 PM writes...

Alpha particles ARE radiation which kills cancer (& normal) cells. I believe a single alpha hit can kill. (By the way, alphas are very short range; holding an alpha emitter is generally harmless since skin stops alphas.)

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10. eugene on August 11, 2012 3:35 AM writes...

Alpha particles are helium nuclei, they do not kill anything. If they are going really fast, then when they hit something and slow down, they release radiation. But I believe it's when they are produced that a gamma ray is being emitted.

Never mind, I found it myself in wikipedia under 'applications'. Unlike what the link says, I don't believe that alphas can't kill. But the gamma rays formed in their production from the parent nucleus certainly can. Being non-radioactive and non-penetrating, they probably limit the damage to non-targeted issue by being not making further gamma rays somewhere down the line.

http://en.wikipedia.org/wiki/Alpha_particle#Applications

Anyway, semantics and all that.

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11. Rick Wobbe on August 11, 2012 8:57 AM writes...

If I weren't so lazy, I would look up references for this, but I recall something similar to this phenomenon has been observed for some anti-infective agents at low doses and/or early in their time-courses. Specific mechanism is undoubtedly different, but I wonder if the general similarity is informative.

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12. Rick Wobbe on August 11, 2012 9:07 AM writes...

Hormesis, THAT's the word I was looking for. Stupid old brain...

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13. gippgig on August 11, 2012 1:33 PM writes...

#10: Alpha particles can kill directly (for example, by slamming into an atom in DNA & breaking its bonds) or indirectly (by hitting a random molecule & producing highly reactive ions & free radicals).
When a nucleus emits an alpha particle the resulting nucleus (containing 2 fewer protons & 2 fewer neutrons) can be in the ground state, in which case no gamma rays are emitted, or in an excited state, in which case one or more gamma rays are emitted to get to the ground state. For use as a targeted anticancer agent an isotope that didn't emit gammas would be best (to minimize nontargeted radiation since gamma rays, unlike alphas, are very long range).
#11: Many antibiotic resistance genes are normally not expressed (repressed) and are turned on by exposure to the antibiotic.

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14. eugene on August 11, 2012 2:26 PM writes...

I don't remember of any example of straight decay to a ground state, but obviously there could be something. It's true that alpha particles are lacking two electrons as they are emitted, so they should be efficient at generating radicals. And the parent nucleus is obviously an electron donor as well.

I don't mean to argue pointlessly, I'm just wondering how this works. I disagree with the kinetic slamming into things explanation for the alpha particle as the only thing they do, but I could accept it. I guess there could be huge cascade effects from losing kinetic energy.

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15. Rick Wobbe on August 11, 2012 7:02 PM writes...

gippig #13, the phenomenon, hormesis, has nothing to do with resistance and has been observed with bacteria, fungi, viruses and, as it turns out, various transformed cell lines. One wonders if these guys just discovered a phenomenon we've known about for over 100 years, except for the fancy Wnt part that is.

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16. Reid von Borstel on August 12, 2012 6:14 AM writes...

9, 10& 11: My father, Jack von Borstel, was the first to show that a single alpha particle aimed into the nucleus of a cell was sufficient to kill it, whereas, if restricted to the cytoplasm, cells could tolerate 20 million alpha particles. However, aiming alpha particles selectively at cancer nuclei from up close is rather problematic.

There have been some reasonable clinical successes with targeted beta emitters (where beta crossfire is the critical mediator of efficient cell kill) such as Yttrium-90, chelated and attached to a targeting antibody, as in Zevalin (targeting CD20 in B cell lymphomas, with a decent incidence of complete responses, generally better than than cold anti CD20 antibodies like Rituxan) or BW 250/183, an Yttrium-90 labelled anti-CD 66 antibody for wiping out covert multiple myeloma in the bone marrow prior to transplant, providing higher local radiation intensity than can be achieved with external radiation, and with much less systemic radiation damage outside the marrow.

Alpha-particle bombardment of the Habrobracon egg. I. Sensitivity of the nucleus.
ROGERS RW, VON BORSTEL RC.
Radiat Res. 1957 Nov;7(5):484-90
PMID: 13485389

Alpha-particle bombardment of the Habrobracon egg. II. Response of the cytoplasm.
VON BORSTEL RC, ROGERS RW.
Radiat Res. 1958 Mar;8(3):248-53.
PMID: 13527611

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17. insilicoconsulting on August 13, 2012 1:02 AM writes...

Developmental biology and cancer are two sides of the same coin. I wonder then how many of the current cancer targets are ones that are differentially expressed in placenta, foetus etc as compared to "normal adults". Drug targets that are then expressed in a cancerous state, comparable to the foetal stage but not normal adults would be interesting.

Maybe, some of the signals and microenvironments in foetal developmental pathways and cancer are similar?

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18. Carl Lumma on August 13, 2012 4:15 PM writes...

As noted above, alpha particles are directly cytotoxic, but only at very short range. This makes them candidates for targeted treatments, i.e. by attaching them to antibodies or receptor-affine peptides. Significant work dates back to the late '90s, but just in 2011-12 there seems to be a lot going on in the literature and I would strongly encourage folks to check it out.

An example nuclide is Bi-213, with decay chain

Bi-213 >>46min B->> Po-213 >>4us a>> Pb-209 >>3hr B->> Bi-209

Bi-209 being classically stable. The betas are low-energy.

Here are just two recent examples

http://ec.europa.eu/dgs/jrc/index.cfm?id=1410&dt_code=NWS&obj_id=14980

http://cancerres.aacrjournals.org/content/early/2011/01/12/0008-5472.CAN-10-1186.full.pdf

-Carl

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19. eugene on August 16, 2012 2:34 PM writes...

Thanks, Reid and Carl and others.

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