herceptin seems to prevent repair of DNA damage caused by chemotherapeutic agents

[Lani]

(at least when her2 translocates to the nucleus) but this article raises the question--why then did the HERA study and the North American adjuvant herceptin trials get such similar results ie giving herceptin alone AFTER chemotherapy (actually quite a long time after) vs giving herceptin and chemo simultaneously

Mol Cancer Ther. 2009 Nov 3. [Epub ahead of print]
Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents.
Boone JJ, Bhosle J, Tilby MJ, Hartley JA, Hochhauser D.

1Cancer Research UK Drug-DNA Interactions Research Group, UCL Cancer Institute, University College London, London, United Kingdom and 2Cancer Research Unit, University of Newcastle upon Tyne, The Medical School, Cancer Research Unit, Newcastle upon Tyne, United Kingdom.
HER2 (ErbB2) is overexpressed in up to 30% of human breast cancers. Preclinical and clinical studies suggest synergy between some chemotherapeutic agents and the humanized anti-HER2 antibody trastuzumab (Herceptin). This study investigated the effects of etoposide and cisplatin on the repair of DNA damage in breast cancer cell lines. We examined the potential significance of HER2 nuclear expression in DNA repair. MCF-7, SK-BR-3, and MDA-MB-453 cells were treated with cisplatin and etoposide. Repair of DNA interstrand crosslinks (ICL) and strand breaks, following incubation with cisplatin and etoposide, respectively, were quantitated by the single-cell gel electrophoresis (comet) assay. Intrastrand crosslinks produced by cisplatin were assessed by ELISA. The effects of trastuzumab were measured in combination with these drugs. Similar experiments were done using HER2-negative MDA-MB-468 cells transfected with HER2 and a construct lacking the nuclear localization sequence. Incubation of breast cancer cell lines with trastuzumab delayed the repair of ICL produced by cisplatin. There were no effects on the repair of intrastrand crosslinks produced by cisplatin, or repair of DNA strand breaks following etoposide treatment. Transfection of HER2 into MDA-MB-468 cells inhibited the repair of cisplatin-induced ICL, whereas transfection of a HER2 construct lacking the nuclear localization sequence did not affect DNA repair. These results indicate that HER2 expression modulates the repair of specific DNA lesions produced by chemotherapy. The effect on ICL repair requires nuclear expression of HER2. Understanding the mechanisms of interaction between DNA-interacting agents and HER2 inhibitors will inform the design of clinical trials and optimize the therapeutic effects of these combinations. [Mol Cancer Ther 2009;8(11):3015-23].

PMID: 19887555 [PubMed - as supplied by publisher]

[Ellie F]

Lani
Please could you help me understand this a bit better. Does this imply that herceptin should be given at the same time as herceptin rather than on it's own?
Ellie

[Rich66]

Wow..total propellerhead piece. Twin propellers.
Am I right in interpreting benefit(damage) to her2 negative cells?

[Chelee]

Rich, I loved your "twin propeller head" comment to Lani. lmao! It really struck me so funny I started laughing. Good one!
(As to this article, I know it's way over my head...but I did try.) Hopefully Lani will explain it?


Chelee

[Lani]

It was only the her2 located in the NUCLEUS which affected the ability to repair DNA damage caused by chemotherapy agents. Her2 normally sits across the membrane between the cell and its exterior, not in the nucleus.
Cytoplasmic/membrane her2 DID NOT in this paper did not affect any DNA repair ability.

How her2 can translocate or otherwise be found in the nucelus
is still being worked out--but the interesting thing is, that the herceptin trials' results in North America did not differ TERRIBLY markedly from those throughout the rest of the world even though herceptin was given concurrently in the former and not in the latter.

The scientists are going to have to look into this much more fully before an explanation emerges, but it may cause them to alter the way they do trials to try to work this out.

[Rich66]

(propellers sputtering)
I wonder if this location of Her2 is somehow related to differing responses to Herceptin. Or..does Herceptin or other therapy trigger the "translocation?
Ummm..

[Laurel]

Whew! I am so glad others were perplexed by this post! I felt so stupid after repeatedly sifting through it I had to reach for a drink! Seriously! I felt piteously dumb! Confidentially, everyone, I still am not at all certain I've got this "jist" of this one....

[Rich66]

You know, it's unusual for an abstract to not have a "conclusion" section. Maybe telling?


Ellie,
Seems like there are studies showing synergies with chemos and pretty much none showing similar or superior effect rates on its own. My sense it is at minimum additive and usually has a chance of being synergistic. But there does seem to be benefit to getting it even if by itself.

Laurel, you haven't lived until you've been "quantitated by the single-cell gel electrophoresis (comet) assay."

[Laurel]

I'm takin' your word on that one, Rich! Whew!

[PatriceH]

How can us with chemo brain even comprehend this?

I guess it's one of those things you just scratch your head and move on

[Hopeful]

why then did the HERA study and the North American adjuvant herceptin trials get such similar results ie giving herceptin alone AFTER chemotherapy (actually quite a long time after) vs giving herceptin and chemo simultaneously

I think the answer is that science has yet to totally understand all the means by which Herceptin works. It has always struck me as funny that they developed this fantastic drug that shows great results, but are still in the dark as to how it works - for example, I have in my files a study of neoadjuvant Herceptin treatment, designed to "elucidate the means" by which it works. Rich66 has posted a review of the mechanisms of action of Herceptin in the articles forum that lists at least 5 different ones. Like alot of things (asprin, for one) I am sure this drug has many more uses that are currently undiscovered.

Hopeful