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Roggenchips, Knoblauch. Chips Cracker Premium, Meersalz. The com- munication between cells relies, gener- ally, on a continuous exchange of chemical signals which, depending on their source and target location, are known variously as hormones, neuro- transmitters, cytokines, mediators, or growth factors.

Every cell of our bodies is able to send and receive such sig- nals and in this way maintains continu- ous contact to all other cells.

This com- munication system guarantees that the different components of the body be- have in a coherent and cooperative fashion, much as if they were following a pre-arranged plan.

A basic principle of intercellular com- munication is that the medium and the message are not identical. In other words, the same signal can provoke dif- ferent responses in different cells for example, reproduction, special func- tions, movement, or death.

Thus, re- cipient cells attribute their own specific meaning to every signal. This job of interpretation is carried out by a highly complex system of interactions between protein molecules.

It is accom- panied by the creation of specific mo- lecular activity patterns, for example, of genes and enzymes, which enable the cell to give an adequate response to external influences.

These protective and emergency reactions are also linked with a well-de- fined pattern of modulation of the activ- ity of certain genes and enzymes.

In view of the fact that communication and cognition are fundamental life process- es, it is easy to understand why cellular signal processing is the subject of in- tense research efforts, especially when one considers that the genetic defects leading to cancer, and also many other diseases, manifest themselves as a malfunctioning of this system.

Here lies the main emphasis of the re- search carried out in the Research Pro- gram Tumor Cell Regulation. Several of its groups are attempting to identify how the pathological changes occurring in the cellular signal processing corre- spond to the various stages of progres- sive tumor development.

Of particular interest are the signal molecules with which the tumor cells can stimulate themselves, thereby, achieving a de- gree of independence from the organ- ism.

The substances concerned are various growth factors and also a group of compounds called eicosanoids, which include prostaglandins, throm- boxanes, leucotrienes, and lipoxins and many other short-lived but highly active molecules.

These are involved in the regulation of nearly all tissue and bodily functions and their role in disease pro- cesses, including cancer, is becoming increasingly evident.

A key role In the signal processing mechanism within the cell is played by 44 Tumor Cell Regulation the biochemical process of protein phosphorylation together with its partic- ipating enzymes protein kinases and phosphatases.

This reaction actually represents - analogous to the electro- chemical impulse in the nervous system - a universal binary code for cellular data processing.

Within the Re- search Program several groups are working to isolate and characterize this type of enzyme and to discover their exact role in physiological and patho- physiological processes.

Protein phosphorylation is also the means by which the genes are regulat- ed. Indeed, the adjustment of the gene activity, and hence protein synthesis, to suit external circumstances plays a cen- tral role in the behavior of cells.

The reg- ulatory proteins that are necessary for this, for example the transcription fac- tors, are components of the cognitive network of the cell.

The regulation of their function - among other things by phosphorylation -, how this regulation is influenced by carcinogenic factors, and the consequences of this for the cell are all being studied in detail using the ex- ample of the transcription factor AP1.

In addition to the phosphorylation en- zymes, the cellular signal processing and the formation of activity patterns also require a molecular switching ele- ment which is provided by molecules known as G proteins.

A pathological overactivation of the G protein Ras is amongst the most common disturbanc- es associated with cancer.

Another topic of study within the Research Pro- gram are the Ran proteins, which be- long to the same family and are re- sponsible for controlling the exchange of material between the cell nucleus and the cytoplasm.

This is a process of vital significance for the cell, essential among other things for cell division or mitosis.

A better understanding of cell division is also the major aim of the in- vestigations of the proteins of the mitot- ic apparatus and the chromosomes.

The communication between cells and the protection against poisonous sub- stances are two processes in which transport proteins play an Important role by facilitating the export of sub- stances.

When such transport process- es are overactivated this can lead, among other things, to the dreaded re- sistance to anticancer drugs chemo- therapy resistance.

These interrela- tions, which are clearly of vital impor- tance In cancer therapy, are being stud- ied by several of the groups of the Re- search Program.

In view of the complexity of the topics, the work carried out in this Research Program demands the combined use of microscopic, cell-biological, biochemi- cal, and molecular biological methods and, thus, a close collaboration between the individual divisions and also with other programs within the Center.

Furthermore, affiliated with this Research Program Is a highly sophisti- cated spectroscopy department which employs the most modern analytical methods.

An approach that holds great potential is chemoprevention. The idea of this Is that suitable substances can inhibit the occurrence of cancer or cause existing tumors to stop growing or even shrink before they reach the stage of malignancy.

A prerequisite for this, however, is a knowledge of the molecular processes that one wants to manipulate. A drug that is frequently discussed in relation to chemopreven- tion is aspirin and also its relatives.

These substances are found to inhibit the development of intestinal cancer In humans. They selectively influence the communication between cells by inhibit- ing the formation of certain signal mole- cules, namely the previously mentioned prostaglandins.

With the emphasis more on treatment than prevention, cell poisons are currently being tried out. Almost all of these have serious side effects which, in combination with the problem of resistance, means that their applicability is quite limited.

But there are good prospects of better controlling the side effects, again by selectively in- fluencing the Intercellular signal trans- mission.

Hence there is reason to hope that existing cancer treatments can be- come more successful. Coordinator of the Research Program: Prof.

Friedrich Marks Divisions and their heads: Pathochemistry: Prof. Volker Kinzel Biochemistry of the Cell: Prof. Dieter Werner Biochemistry of Tissue-Specific Regulation: Prof.

Friedrich Marks Differentiation and Carcinogenesis in vitro: Prof. Norbert Fusenig Tumor Biochemistry: Prof.

Dietrich Keppler Molecular Biology of Mitosis: Prof. Herwig Ponstingl Signal Transduction and Growth Control: Dr.

Peter Angel 45 3. We have developed a cell culture test which evaluates skin-irritating chemicals by measuring a central trigger mechanism in skin inflammations.

Specifically, we focus on the release of the primary me- diators of inflammation, interleukin-1 a and arachidonic acid from human kerat- inocytes.

This reaction represents a general cellular response to the effect of substances that irritate the skin. The validity of the test was confirmed in ex- periments on humans.

Clinical symp- toms of inflammation such as erythema and a disturbance in the barrier charac- teristics of the skin, as well as the local release of arachidonic acid and its re- sulting products, correlate well with the data measured in the cell culture.

On the basis of these findings, it ap- pears that this procedure may be a suit- able alternative method for certain ani- mal experiments. It is possible to fur- ther develop this test to detect certain aspects of carcinogenic effects.

From Animal Experiment to Cell Culture Test Thousands of new chemicals are devel- oped every year in the pharmaceutical, cosmetic, food, and chemical indus- tries.

Before such substances can be used, they must be tested for harmful effects, such as whether or not they cause Inflammations, have caustic ef- fects, are associated with deformities, or are carcinogenic.

The legislature re- quires various animal experiments for this very purpose. Although we cannot yet do without such experiments in light of the current state of scientific knowl- edge, their value is being examined in an increasingly critical manner.

Not only do strong public feelings with respect to animal protection and animal rights play a role here, but also economic and sci- entific arguments are being openly dis- cussed.

Testing certain chemicals for their skin-irritating properties can serve as an example. For this purpose, the procedure developed by John Draize in is still being used to this very day.

In this method test substances are placed on the skin or on the eye of a rabbit; the symptoms of an acute irrita- tion are observed over the course of several days and are classified accord- ing to their degree of severity.

Such symptoms include the reddening of the skin erythema , which can be traced to an increased blood flow in the superfi- cial vessels and swelling edema that occurs when the blood vessel walls be- come permeable and blood plasma passes into the tissue.

Although these symptoms are evaluated according to a standardized key and the test satisfies the requirements of governmental au- thorities throughout the world, doubts exist about its reliability.

For example, the reproducibility of results obtained in different laboratories and their transfer- ability to humans has been questioned.

Furthermore, the measured inflamma- tory reactions can prove to be very bur- densome for the experimental animal since they are usually accompanied by pain.

Therefore, the Draize Test stands under fire both from the public and from animal protection organizations.

In par- ticular, many people no longer under- stand the need to test products for per- sonal hygiene In animal experiments.

The European Union has yielded to this public pressure In its sixth amendment to the EU Cosmetic Guidelines. As of January 1, , animal experiments are to be generally prohibited for testing 46 Research without Animal Experiments the ingredients of cosmetic substances.

However, there is reservation; scientif- ically valid alternate methods must be available. The legislature will only rec- ognize such alternate methods if they are equivalent to the "gold standard" as defined by the Draize Test.

The development of alternate methods is complicated by the fact that the in- flammatory process is a complex reac- tion in the human body.

Many types of cells work together and its course also depends on the nature of the irritant. Such a process, in all its details, cannot be mimicked in cell and tissue culture.

We be- lieve that we have identified such fun- damental processes specifically for the inflammatory reaction of the skin.

On this basis, we have developed a cell culture test for chemicals that irritate the skin; it should at least partially re- place conventional animal experiments.

Since inflammatory processes In the skin and in other tissues can promote, although not cause, cancer such a test should also be able to detect certain aspects of carcinogenic effects.

In fact, the idea for the test arose out of many years of research that focused on the development of skin cancer.

The Response of the Skin to Irritants As the protective organ of the body, the skin responds very sensitively to harm- ful influences In the environment.

An ef- fective barrier is found in the horny layer at the surface of the skin; It Is formed from dead epidermal cells or keratinocytes and is sealed with fat-like substances.

In the next step, white blood cells leukocytes and defense cells of the immune system are attract- ed.

They all communicate by means of hormone-like signal molecules that are called mediators of inflammation. Thereby, the characteristic symptoms of inflammation result: erythema, edema, a feeling of heat, pain, and pos- sibly pyogenesis.

Additionally, the epi- dermis is strengthened through acceler- ated cell production and cornificatlon hyperplasia. The keratinocytes in the epidermis appear to play a key role in triggering this cascade of reactions.

As a kind of interface between the body and the environment, these cells are specialized to respond to stimuli by re- leasing mediators of Inflammation and, thereby, to set in motion the protective and defense functions.

Several of these signal substances are released within a few seconds, others with some delay. For example, members of the eicosanoid family Include prosta- glandins, leukotrienes and the hydroxy- eicosatetraenoic acids.

Common to all primary mediators of inflammation is their storage within the cell so that they can be immediately released as need- ed.

It is also typical that they appear ei- ther alone or together with other active substances in all phases of the Inflam- matory process.

Their role is one of stimulating keratinocytes and other types of cells to synthesize and release additional mediators so that the cas- cade of protective and defensive reac- tions is set in motion.

The Release of Inflammation Mediators in Cell Cultures is a Measure of the Skin-Irritating Effect The release of interleukin-la and arachidonic acid from keratinocytes is a process that plays a central role in the inflammatory reaction of the skin.

Fur- thermore, it can easily be measured in tissue culture. Is it possible to assess the skin-irritating effect of chemicals in this manner?

In order to answer this question, one first had to prove that treating cell cultures with skin-irritating substances led to the release of the named mediators.

In order to avoid problems associated with the differ- ences between humans and animals from the very beginning, we chose human keratinocytes HPKII cells for these experiments.

These cells in fact respond to 15 structurally different test substances by releasing Interleukin-la, arachidonic acid and eicosanoids.

Arachidonic acid and eicosanoids were determined by using radioactively marked substances. Before the test, we grew cells in the presence of 14C arachidonic acid which was taken up 47 and incorporated into the lipids com- prising the cell membranes.

After treat- ing the cells with the test chemicals, the arachidonic acid and the eicosanoids released into the nutritive solution was extracted using organic solvents, sub- sequently separated by thin layer chromatography, and finally quantified with respect to Its radioactivity.

At the same time, the release of interleukin-1 a was measured with an Immunological enzymatic test; an enzyme coupled to a specific antibody catalyzed a color re- action that was a measure for the quan- tity of interleukin.

A vitality test was used to evaluate a cell-damaging ef- fect. The test was based on the princi- ple that only living cells can convert the colorless substance MTT to an insolu- ble, purple-black dye formazan.

The quantity of the dye corresponds to the proportion of living cells. The release of interleukin-la and arachidonic acid depends on the type and quantity of the test substance.

The greater the irritating effect and the dose of a chemical, the greater was the quantity of inflammation mediators re- leased by the cells.

Clear differences were observed in the time course of the reactions: depending on the substance, the release of mediators either oc- curred quickly, delayed or late.

A quick arachidonic acid response was not al- ways coupled with a quick interleukin- 1a response. Those substances that produced a quick cell response were not always the most effective Irritants.

Therefore, it was important to measure the release of mediators over a longer time period in order to be certain of de- tecting the irritating effect of a chemical.

In testing on animals, the irritating effect of the chemicals increases from top to bottom. Those substances marked by a star were also tested on humans in order to evaluate the reliability of the results obtained with the new method is elicited.

In this context, we noticed that the cells reacted more sensitively to the release of arachidonic acid than to Interleukin-la.

This Is probably due to the fact that the cells must be quite significantly damaged before they re- lease interleukin-la while the arachi- donic acid response requires signifi- cantly less irritation.

Irrespective of this, both quantities taken together provided the most reliable information. Confirming the Method in Humans Are the results obtained with the cell culture an adequate measure of the ef- fect of chemicals on the intact skin?

This was so even without considering the problem of data transferability from ani- mals to humans. After receiving permis- sion from an ethics commission and from governmental authorities and also in collaboration with the pharmacologi- cal division of Schering AG, we con- ducted a study to evaluate our results in humans.

For this purpose, the specific substances were applied in various concentrations to the inner side of the lower arm and the treated skin areas were covered with special chambers for an entire day.

For the next three days, a physician evaluated the visible symptoms of skin irritation, especially erythema and edema. Additionally, the extent of skin damage was measured.

An especially sensitive measure for this Is the perme- ability of the epidermis for tissue fluid, so-called transepidermal water loss.

It was detected with a method that is de- scribed as the noninvasive measure- ment of evaporation among dermatolo- gists. During a second round of treat- ment, the release of arachidonic acid, eicosanoids, and Interleukin-la in the 48 Research without Animal Experiments Fig.

Various test fields are applied to the underarm of a test subject A. In order to detect damage to the skin barrier, the outflow of water from the cutis is measured B.

In the blister, which has been artificially created by suction on the cutis, messenger sub- stances of inflammation collect as they are released by the skin cells C.

Sodium iauryl sulfate, which is contained in cleaning agents, causes a reddening of the skin D skin were quantitatively analyzed. Ran- domly selected participants in the ex- periment had the test substances ad- ministered to their skin in quantities that corresponded to the previously deter- mined individual doses for a given irri- tant.

By applying negative pressure, skin blisters were produced above the test areas. The tissue fluid that collect- ed in the blisters over time contained the mediators of inflammation that had been produced by the skin cells.

This pro- cess quantitatively determined an en- tire spectrum of eicosanoids PGDg, PGE 2 , PGFgOC, G-koto-PGFgOc, LTB 4 , 5-, 12, HETE in addition to the arachi- donic acid.

It was discovered that a skin-irritating effect caused by test chemicals always correlated with a clearly elevated eicosanoid level in the blister fluid.

Barrier disturbances of the skin which are recognizable by in- creased water permeability were only caused by strong irritants. It Is especial- ly important that the irritating effect on the intact skin predominantly agreed with the data measured in the cell cul- ture.

This was demonstrated by a com- parison of eight chemicals. However, the concentrations for Interleukin-la fluctuated so significantly from test per- son to test person that a statistically certain result could not be obtained.

Conclusion We understand our studies to be a step towards developing a cell culture test to evaluate the Inflammatory effect of chemical substances.

In this context, we proceed from a more exact knowl- edge of the fundamental molecular mechanisms Instead of measuring more or less unspecific symptoms as is done in conventional procedures.

The keratinocyte cell line HPKII , which we used, can be easily kept in cell culture without any problems. The immunological enzymatic test and marking with isotopes are both stan- dard procedures that can be conducted in any modern laboratory.

However, both the economy and the ease of use of the test would still be significantly im- proved if one could manage without ra- dioactive substances by, for example, developing an immunological test for arachidonic acid.

If one bears in mind the complexity of the inflammatory process and the ap- parently very different mechanisms of action exhibited by inflammatory chemi- cals, the relatively high significance of such a simple test may at first glance prove surprising.

Lancet , Muller-Decker, K. WIssenschaftliche Herausfor- derungen und Perspektiven. Spektrum Aka- demischer Verlag, Berlin-Heidelberg-Oxford Fig.

Karin Muller-Decker Prof. Friedrich Marks Division of Biochemistry of Tissue-Specific Regulation In collaboration with Prof.

Werner Raff Dr. Andrei Kecskes Dr. Wolfgang Seibert Ines Zimmer Department of Clinical Pharmacology, Sobering AG, Berlin Prof.

Wolf-Dieter Lehmann Central Spectroscopy, Deutsches Krebsforschungszentrum Participating scientists Dr. Gerhard Furstenberger Thomas Heinzelmann 50 Approaches to Counteract Multidrug Resistance 3.

Many malignant tu- mors initially respond to treatment with cytotoxic or cytostatic agents but devel- op subsequently a resistance to sever- al, structurally diverse anticancer agents.

This phenomenon is known as multidrug resistance of tumors. The mo- lecular mechanisms underlying the mul- tidrug resistance of malignant tumors and the development of drugs counter- acting this resistance are intensively in- vestigated by scientists in research in- stitutions, clinical research laboratories, and in the pharmaceutical industry.

Different mechanisms lead to multidrug resistance of malignant tumor cells. An increasing number of molecular mech- anisms causing multidrug resistance was recognized during the past ten years.

These distinct membrane pumps function in the transport of different drugs across the plasma membrane of tumor cells into the extracellular space.

The membrane pumps encoded by the MDR1 and MRP1 genes have different amino acid sequences and a different substrate specificity with respect to the compounds transported out of tumor cells.

Additional mechanisms of drug resistance include those caused by an increased inactivation of cytotoxic drugs by binding to glutathione or the resistance of tumor cells to the signals causing programmed cell death apop- tosis.

Resistance to structurally diverse cyto- toxic agents by ATP mediated export of Fig. Vincristine is such a product. Along with ATP and glutathione, it can be transported out of the tumor cell by the muitidrug resistance protein MRP1 drugs from tumor cells.

It has been es- tablished that the MDR1 gene encoded P-glycoproteIn, an export pump with a molecular mass of about kllodal- ton, transports structurally diverse drugs including anthracycline-based cy- tostatic agents, vinca alcaloids, or the antimitotic drug taxol paclitaxel.

These anticancer drugs are widely used in the clinical treatment of hemat- ological cancers, ovarian cancer, and mammary cancer.

Effective concentra- tions of these anticancer agents may be prevented by the action of MDR1 P- glycoprotein. It has been recognized more recently that MDR1 P-glycopro- tein transports not only exogenous cy- totoxic drugs into the extracellular space but also a number of structurally different endogenous lipophilic com- pounds.

This membrane protein is often ex- pressed in tumors which do not have increased levels of MDR1 P-glycopro- tein and which are resistant to several anticancer drugs.

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