Some carcinomas were very strongly affected by doxorubicin, whereas others showed no or only moderate effects. In general, tumors with high incorporation rates of nucleic acid precursors showed more pronounced inhibitory effects and vice versa Similar results were obtained with lung carcinomas Survival curves differed, if patients were distributed into two groups on the basis of the in vitro short-term test with doxorubicin.
Patients with in vitro resistant tumors died sooner than in vitro sensitive ones. Lung cancer patients, who refused chemotherapy lived on average only as long as patients with in vitro resistant tumors 8. In a multi-centric trial conducted by nine different hospitals, results obtained by the in vitro short-term test were compared with the clinical response of patients The remaining patients received different therapy regimens. Using the in vitro short-term test, dose—response curves were generated for doxorubicin as well as 5-fluorouracil and 4-OOH-cyclophosphamide the in vitro active metabolite of cyclophosphamide.
A Comparison of results of the in vitro short-term test and clinical chemotherapy of human tumors. Closed symbols, tumors responsive to clinical chemotherapy. Open symbols, Tumors non-responsive to clinical chemotherapy. Overall survival curves of patients with B ovarian carcinoma or C lung carcinoma separated into either resistant or sensitive groups according to the in vitro short-term test results. D Of the 32 patients with previously untreated adenocarcinoma of the lung stage III , 14 were treated with surgery alone group S and 18 were treated with surgery plus chemotherapy group CT.
E However, when the same data were analyzed on the basis of the in vitro short-term test, a different pattern appeared. Of them, 76 had been classified as resistant and 75 as sensitive by the in vitro short-term test. The 75 in vitro sensitive tumors showed the following clinical courses: Thus, drug resistance was predictable with high accuracy, but not drug sensitivity.
Furthermore, drug resistance has been detected in vitro by doxorubicin with high accuracy, even if this substance had not been included in the clinical therapy regimens. By contrast, it was not possible to predict in vitro drug-specific sensitivity in primary, non-pre-treated human carcinomas with the same degree of accuracy. The vast majority of publications reported that the prediction of drug resistance was possible with much higher accuracy than prediction of drug sensitivity.
The numbers of patients of all published papers exceeded 15, Remarkably again, drug resistance could be predicted with high reliability, but not sensitivity. This synopsis of the published literature of four decades impressively illustrates that the concept of prediction of chemosensitivity was not validated. By contrast, the determination of drug resistance was reliable independent of tumor type, test assay, and drug used in these in vitro tests. Patients, whose tumors were resistant in the in vitro short-term test, died earlier than patients, whose tumors were in vitro sensitive.
This cooperative clinical trial confirmed the feasibility to predict resistance of cancer in vitro before starting chemotherapy and the relevance for clinical treatment. Thirty-two patients with previously untreated adenocarcinoma of the lung stage III, pT, pN were included in this investigation.
Fourteen patients were only treated by surgical procedures group S , and 18 patients were additionally treated with cytotoxic drugs CT group. However, if we reanalyzed the same data on the basis of the in vitro short-term test results, a different pattern emerged. As expected, the survival times of patients treated with surgery, but not chemotherapy, did not correlate with the in vitro test results Thus, the observed differences in survival times of patients treated with surgery plus chemotherapy were specific and can be attributed to drug therapy.
Again, we have compared our own data with published results of more than patients in the literature. This has been observed in the vast majority of patients independent of which tumors they were suffering from or which cytostatic drug has been used for testing. If a tumor responded to doxorubicin by means of the in vitro short-term test, in the majority of cases similar effects can be detected with other cytostatic agents, i.
Statistically significant correlations existed between the inhibitory effect of doxorubicin, daunorubicin, 5-fluorouracil, actinomycin D, and cyclophosphamide 8. A Cross-resistance of doxorubicin to daunorubicin, 5-fluorouracil, actinomycin D, and cyclophosphamide in various human tumor types as measured by the in vitro short-term test. B Hierarchical cluster analyses of response of clinical tumor specimens toward different antitumor drugs from different drug classes: Dendograms obtained from clustering of 59 diverse tumors, 38 lung carcinomas, and 21 leukemia [data are taken from Ref.
In the s and s, a resistance phenomenon has been investigated termed multidrug resistance MDR , which is caused by the drug efflux transporter P-glycoprotein. MDR comprises cross-resistance of tumor cells to anthracyclines, Vinca alkaloids, taxanes, and epipodophyllotoxins, but not to alkylating agents and antimetabolites 88 , Therefore, we were interested, whether or not the cross-resistance profile observed in our approach was compliant with the MDR phenotype We analyzed 59 tumors of different origin for their in vitro resistance to anthracyclines doxorubicin, daunorubicin , antibiotics dactinomycin, bleomycin , antimetabolites 5-fluorouracil, methotrexate , epipodophyllotoxins mitopodozide , and alkylating agents procarbazine, triaziquone by means of the in vitro short-term test.
As a next step, we performed hierarchical cluster analysis, which may be more suited for an integrated approach to understand the complexity of drug resistance. We divided the dendrogram into six clusters and correlated them with the doxorubicin results.
Introduction
This indicates that resistance to nine compounds from different drug classes antibiotics, antimetabolites, epipodophyllotoxins, and alkylating agents significantly correlated with resistance to doxorubicin. This opens the possibility to predict the responsiveness of tumors to a broad range of cytostatic drugs by using solely doxorubicin as a reference drug. Cluster analysis using the data for 5-fluorouracil and 4-OOH-cyclophosphamide allowed the separation of three clusters. To validate this result on lung cancer as a solid tumor type, we subsequently used leukemia as single cell cancer.
In addition to a possible value of doxorubicin as reference compound for the in vitro short-term test, another conclusion of these investigations is that tumors exert cross-resistance profiles that are broader than the classical P-glycoprotein-mediated MDR phenotype. Our cluster analyses revealed that clusters of sensitive or resistant tumors could be predicted by one single drug, doxorubicin.
This speaks for the high predictive power of doxorubicin to detect broad spectrum resistance. The pleiotropic modes of action of doxorubicin might explain, why doxorubicin is capable of predicting broad spectrum resistance. This enables to conduct predictive tumor tests with drugs not included in the therapy schedule.
According to our investigations on human tumors, tests using doxorubicin appear to be sufficient to detect drug resistance. Therefore, the in vitro short-term test should be generally not used to find the most effective compound in individual tumors, but merely to determine whether a tumor responds at all to any chemotherapy. Having in mind that tumors tend to be sensitive or resistant not only to single but also to multiple drugs at the same time, it can be speculated that multiple factors rather than single mechanisms may account for broad spectrum or pan-resistance 87 , For this reason, we investigated a battery of diverse factors for their expression levels in lung tumors and compared these expressions with the results of the in vitro short-term test.
The rationale for these analyses was substantiated by the fact that increasing evidence emerged in the literature for a variety of many different drug resistance mechanisms, which are all operative in clinically resistant tumors 5 , 13 , 88 , 91 — The question arises, as to which resistance factors may be recognized by the in vitro short-term test.
Recent Results in Cancer Research | Tanum nettbokhandel
Therefore, we determined a total of more than 50 resistance-related factors in 94 human non-small cell lung carcinomas by immunohistochemistry These factors can be categorized as resistance proteins, proliferation-related proteins, oncoproteins and tumor suppressor proteins, proteins regulating apoptosis, and angiogenic factors. Of them, the expression of nine proteins directly correlated and another 19 proteins inversely correlated with resistance to doxorubicin. These histograms demonstrate that the number of tumors with high protein expression levels as determined by semi-quantitative immunoscores increased with doxorubicin resistance.
Relationship between the expression of resistance factors in 94 non-small cell lung carcinomas immunohistochemistry and resistance to doxorubicin as determined by the in vitro short-term test. A Representative examples of factors directly correlating with resistance. B Representative examples of factors inversely correlating with resistance. C Oncobiogram of resistance factors in sensitive tumors dotted line and resistant tumors bold line. E Number of resistance markers in relationship to the degree of resistance.
Data are taken from Ref. Here, rather low than high protein expression was related to doxorubicin resistance. Hence, the number of tumors with high expression of these proteins was higher in sensitive tumors. As a next step, we calculated the mean protein expression values of all sensitive or resistant tumors and plotted them in an oncobiogram.
It can be clearly seen that the mean expressions of all of these factors were lower in sensitive tumors compared to resistant ones.
Chemosensitivity Testing in Oncology (Recent Results in Cancer Research)
These analyses clearly indicate that we have to take multiple rather than single factors into account as mode of action of drug resistance. To prove this assumption, we determined the number of resistant tumors co-expressing more than one resistance factor. This clearly speaks for the multifactorial nature of drug resistance and that single resistance factors are not sufficient to explain resistance phenomena in clinical lung tumors.
In addition, we tested whether combinations of resistance factors may improve the prediction of the degree of resistance. Data obtained from multiple sources, including in vitro drug resistance testing, immunohistochemical determination of resistance-related proteins, and clinical data, indicate that no single drug resistance mechanism can explain drug resistance.
Resistance mechanisms are numerous and diverse. They depend on the detoxifying capacity of cells, tissue-specific factors, repair capacity, drug delivery, cell proliferation, angiogenesis, apoptosis, and many other factors. Additionally mutation or amplification of specific genes involved in protective pathways as well as the mutation of different oncogene or suppressor genes may be responsible for resistance to chemotherapy.
It becomes evident that cancer cells utilize multiple pathways to overcome the cytotoxic effect of drugs used during chemotherapy. Resistance tests should, therefore, recognize these pathways. Our studies attempted to discover the important cellular predictive factors. A key future challenge involves determining the relative contributions of each of these mechanisms. During the past four decades, various in vitro test procedures have been developed used to test sensitivity or resistance. Kubota and Weisenthal reported on in vitro and in vivo results in gastrointestinal tumors Of in vitro assays, were sensitive and resistant.
Our data are in agreement with all these investigations.
Nevertheless, none of these predictive in vitro tests have been clinically established for routine diagnostics. This raises the question as to why clinical translation did not take place, despite numerous investigations speaking for the feasibility of such test systems. An explanation might be the predictive accuracy to detect sensitive and resistant tumors. Hence, the correct conclusion from these data is that all these methods are not reliable enough as clinically useful chemosensitivity tests.
Recent Results in Cancer Research
However, at the same time it can be stated that drug resistance can be predicted with high reliability. The reasons for this striking difference in predictive power to distinguish between sensitive and resistant tumors may be numerous. Chemosensitivity of tumor cells detected ex vivo under artificial laboratory conditions does not necessarily comply with the specific situation of a patient. For instance, effective levels of antineoplastic agents in tumors may not be reached, if tumors are poorly vascularized. Hepatic biotransformation of drugs or interaction between drugs may also play a role in vivo.
For these reasons, false-positive results sensitive in vitro , but resistant in vivo can be expected to occur more frequently than vice versa. A major concept of all the different predictive in vitro tests was to identify drugs a priori which tumors are most sensitive to, in order to use them for subsequent therapy. Hence, scientists and oncologists alike were hunting for the optimal chemosensitivity test.
The facts after all these years of research teach us that it may not be possible to find such an optimal test system. Therefore, it is time now to rethink and question this concept. Instead of testing chemosensivity, these in vitro tests may be used to identify those tumors that are drug resistant with the aim not to treat them with chemotherapy at all.
Prediction of Cancer Drug Resistance and Implications for Personalized Medicine
Nowadays, the situation is changing, as novel treatment options are emerging. Patients diagnosed as being drug resistant with the help of such predictive tests may be treated with other therapy strategies, such as antibody therapy, adoptive immune therapy, hyperthermia, and in the future may be also with aptamer therapy, gene therapy, and others.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Oncol v. Published online Dec This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology. Received Aug 23; Accepted Nov The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Drug resistance still impedes successful cancer chemotherapy. Introduction Chemotherapy of malignant tumors is essentially based on the results of prospective, randomized, double-blind phase III studies and corresponding clinical guidelines.
Detection of Acquired Resistance The usefulness of any resistance test depends on the degree, to which in vitro results are correlated with clinical results. Open in a separate window. Detection of Inherent Resistance Walker carcinosarcoma and neurosarcoma both grown subcutaneously as solid tumors in rats provide suitable models as rapidly and slowly growing tumors, respectively.
Clinical Studies Survival curves differed, if patients were distributed into two groups on the basis of the in vitro short-term test with doxorubicin. Table 1 Predictive value of drug resistance assays. Assay Tumor type No. Table 2 Prognostic value of drug resistance assays. Broad Spectrum Resistance If a tumor responded to doxorubicin by means of the in vitro short-term test, in the majority of cases similar effects can be detected with other cytostatic agents, i. Doxorubicin is transported by P-glycoprotein and, therefore, is involved in the MDR phenotype.
Therefore, doxorubicin can predict response to antibiotics, Vinca alkaloids, and epipodophyllotoxins. The activity of doxorubicin is dependent on the proliferative activity of tumor cells. Therefore, doxorubicin may predict the responsiveness of tumors to other drugs, which also act in a proliferation-dependent manner, such as antimetabolites, i. Because alkylating agents also damage DNA, doxorubicin may predict the response to alkylators, such as 4-OOH-cyclophosphamide.
Doxorubicin as well as alkylating agents generates reactive oxygen species and radical carbon-centered molecules. This represents another explanation for the predictive power of doxorubicin toward alkylating drugs.
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The Multifactorial Nature of Cancer Drug Resistance Having in mind that tumors tend to be sensitive or resistant not only to single but also to multiple drugs at the same time, it can be speculated that multiple factors rather than single mechanisms may account for broad spectrum or pan-resistance 87 , Conclusion Data obtained from multiple sources, including in vitro drug resistance testing, immunohistochemical determination of resistance-related proteins, and clinical data, indicate that no single drug resistance mechanism can explain drug resistance.
Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments We are thankful for Mrs. Ilona Zirbs for secretarial assistance. Funding This paper has been performed with intramural funding.
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