Cancer Therapy: Cudgel back in the Sack

30. September 2009
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If you try to kill even the last cancer cell with tough chemotherapy you will often find out that you achieved the opposite. The resistant successor generation proliferates even faster. An American bio-mathematician believes in a better cancer therapy along the lines: “Let live and survive”.

Some wars you just cannot win: Especially if the enemy permanently changes his tactics and is not impressed – neither by canons nor by huge armies. In agriculture, the integrated plant protection has discovered that lethal use of poison is not always the best solution, because the apparent victory over those pests is followed by their children’s children – untouchable by the poison.

Sensitive and persistent tumors

Perhaps oncologists might be able to learn from ecologists. In a Nature-article, Bob Gatenby, professor at the Moffitt Cancer Center in Florida in the department “mathematical oncology”, just recently advocated renunciation of the “kill-as-much-as-you-can-principle”. His alternative: An adaptive chemotherapy for tumors where the highly dosed cancer drug does not provide any better chances for survival.

Gatenby certainly does not want to advertise his idea as the universal solution for all types of cancer. 90 to 95 percent of Hodgkin-lymphoma or germ cell tumors such as testicular tumors can be healed with aggressive chemotherapy. Here apparently the extinction of that many tumor cells is successful enough so the own immune system manages to finish off the rest. Other types of cancer such as for example an advanced colon carcinoma or bronchial carcinomas obstinately resist nearly any chemotherapy. Then again others are granting the physician a temporary lift just to reappear later as a resistant lump of cells. The Swiss oncologist Thomas Cerny published in the FAZ (Frankfurter Allgemeine Zeitung, German newspaper), that the high dose chemotherapy demonstrably shortens the life of the patient.

Resistents with growth disadvantage

Mostly tumors are anything but a gathering of identical clone-children. Especially metastases lose the majority of their relation characteristics in due course of their development. According to the tumor biologist from Regensburg/Germany, Christoph Klein even as much as that we cannot determine any more who originates from whom. This highly concentrated poisonous broth takes away the disadvantage of those few resistant cells in the clone they have compared to their sensitive brethren. They have to repair their DNA faster, pump out toxic agents from the cell or at least come up with an alternative way of metabolism which blocks the agencies. The price to pay is fitness and growth advantages, for example resistent lung cancer cells against Gemcitabin are less proliferate, invasive or also less mobile than sensitive cells.

But if you do not eradicate the sensitive cells completely and only deplete their number controlled, you don’t assist the progeny of the heavily armed amongst the bad guys as well. But no study yet shows whether this approach brings vital survival advantages into the clinic. But at least in the lab of Gatenby the idea works. His colleagues made human cells of an ovarian carcinoma grow into a tumor in mice to treat them afterwards with high dosed carboplatin or – depending on the growth – with milder doses. This aggressive method showed quicker results but the resistant cells growing later soon cost the mice’s lives. On the other hand, mice as well as tumors survived in the other test branch in a stable balance.

Psychological and scientific obstacles to the target clinical practice

Clinical oncologists engaged in this issue as well. As DocCheck learned from Dirk Jäger, head of the Nationales Centrum für Tumorerkrankungen (national center for tumor diseases) in Heidelberg/Germany, mainly solid therapy resistant tumors qualify for such a therapy. At the same time you cannot heal advanced breast carcinomas but treat them into a “stable-disease-condition”. In these cases, chemotherapy does not only have the purpose of eliminating tumor cells but also to support the own immune system. “A mild chemotherapy”, says Jäger, “adjusts immune suppressing factors downwards and creates a pro-inflammatory environment”, which encourages an anti-tumor answer.

It will not be an easy task to convince patients and physicians to treat cancer like a chronic disease and not like for example an infection. Some cancer therapies might be similar to an insulin shot for diabetics or the life-long admission of immunosuppressive medications after organ transplantations. In addition to a renunciation of entrenched ways of thinking, side effects of some therapies might turn into a problem. Temporarily and high-dosed, the toxicity of some agents is only just tolerable, but an admission over years? Here as well it will pay to make use of the interaction between tumor and immune system and Gatenby suggests trying suitable immunotherapies.

Searching for the stable balance

But what would a ”stable“ balance between tumor and body look like? Other than with metronomic or maintenance-therapy options, Gatenby pleads for an alignment according to size of tumor and according admission of drugs. Will this be enough to continue keeping the number of resistant cells low? The so far mostly theoretical approach only works of sensitive cells have a large fitness-plus over the resistant ones. Gatenby: “We are already making tests on how fast sensitive cells manage to eliminate the resistant cells again as soon as we stop giving chemotherapeutics.

The innovative strategy in treating cancer is not supposed to and will not curb the development of effective tumor therapeutics. Healing the patient will remain the first and overall target of each treatment – something Gatenby and other oncologists fully agree on: “But in some situations a stalemate is more precious than a short-term glorious victory.”

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