Ex vivo programmed cell death and the prediction of response to chemotherapy

Abstract

Since the earliest introduction of cytotoxic chemotherapy, investigators have pursued laboratory techniques designed to match patients to available drugs. Most of the work, published through the 1980s, reflected the prevailing view of cancer as a disease of dysregulated cell proliferation. Noteworthy, the description of apoptosis and programmed cell death, fundamental to our modern understanding of human tumor biology, did not occur until well after the heyday of in vitro chemosensitivity testing. By incorporating the modern tenets of carcinogenesis associated with perturbations in cell survival we can now re-examine laboratory assays of drug response in the context of drug-induced programmed cell death. Although there is interest in the use of genomic analyses for the prediction of chemotherapy response, the painful recognition that genotype does not equal phenotype will continue to limit broad application of these platforms. Biosystematics instructs that biological pathways rarely follow predicted routes. Efforts to force human biology to behave according to preconceived scientific dictates have proven costly and unsuccessful. Whole-cell experimental models with the capacity to evaluate all the operative mechanisms of cellular response to injury, acting in concert, provide valid tools for the study of human cancer. Educated by cellular behavior, we can expeditiously examine molecular processes of interest. This article briefly reviews the history of whole-cell experimental models of in vitro chemosensitivity testing then focuses on cell-death measures as the most robust predictors of clinical outcome in human cancer.

In vitro sensitivity testing of minimally passaged and uncultured gliomas with TRAIL and/or chemotherapy drugs

“…For these reasons, it is also important to examine orthotopic models of cancer. Notwithstanding these considerations, in vitro apoptosis data do tend to correlate with patient responses in cancer types for which truly effective drugs exist (Nagourney, 2006). The dearth of effective drugs for treating glioma has limited assessment of the predictive value of in vitro sensitivity testing for this tumour type.…”

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“…The young woman had "no measurable genetic aberrancies" from a panoply of 370 cancer-causing exomes, while the young man's tumor revealed no somatic mutations and only two germ-line, neither of which had any clinical or therapeutic significance [18].…”

“…Moreover, the composition of ECM also shows great heterogeneity among various tumors and among tumors of histological equivalence and uniformity, hence, uniqueness, distinctiveness individuality. [17] Yang, et al goes on to state" that chemotherapeutic treatments for cancer can effectively reduce tumor mass, but the disease often relapses due to the manifestation of these cancer stem cells (CSC) populations [18]. Thus the tumor now contains a small number of tumor-forming, self-renewing, CSCs within a population of non-tumor-forming cancer cells [11].…”

“…"Seven out of ten patients diagnosed with cancer will be prescribed a drug that does not work well or has severe side effects there is an enormous need in the market for better products that can stratify the patients prior to prescribing" a treatment." [18] To that end, today there evolves a growing interest in personalized medicine for tools that can assist and guide oncologists to the most efficacious therapies for their patients. Combining bioinformatics with theranostics will help to close the gap that exists in early diagnostics, thereby developing a rational approach to effectively manage this devastating disease.…”

“…[18,20,21] Von Hoff [22] proposes that the" objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study [23] suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs." For example, Nagourney [16] reports that "a 32-year-old female with an extremely rare malignancy that arose in her kidney AND a 33-year-old gentleman with widely metastatic sarcoma; both had undergone aggressive multi-modality therapies including chemotherapy, radiation and surgery-suffered significant toxicities-both of their diseases had progressed unabated; both patients had undergone genetic profiling.…”