Induced Differentiation of Neoplastic Cells

1 Jun

As discussed in earlier chapters (Chapters 6, 10, and 14), the chemical induction of differentia- tion of neoplastic cells has been achieved in systems studied in vitro. Lotem and Sachs (1981) and Honma et al. (1997) have reported the inhibition of leukemia development and the prolonga- tion of survival time of mice inoculated with myeloid leukemia by the administration of various chemical inducers of differentiation. In the human in vivo, the principal example of the effective- ness of induced differentiation in the treatment of specific neoplasia is the use of all-trans-retinoic acid in the treatment of acute promyelocytic leukemia (cf. Tallman et al., 1997). These and other studies have demonstrated the effectiveness of all-trans-retinoic acid in inducing or maintaining remission and improving overall survival when compared with chemotherapy alone. Other exam- ples of effects of differentiating agents in vivo include high-dose methylprednisolone in children with acute promyelocytic leukemia (Hiçsönmez et al., 1993) and the use of tetradecanoylphorbol acetate, an effective skin tumor–promoting  agent, in patients with myelocytic leukemia (Han et al., 1998). The theoretical potential for this modality is great, especially since little or no toxicity is associated with the therapy; but in the examples thus far studied in both humans and animals, the effects require continued administration of the differentiating agent. The usual history in the human is that eventually neoplasms will escape the differentiating effect for a variety of mecha- nistic reasons (Early and Dmitrovsky, 1995). In addition, the theoretical combination of multiple differentiating agents may prove to be effective in the future (Taimi et al., 1998).

Antiangiogenesis as an Approach to Chemotherapy of Cancer

As noted in Chapter 18, the importance of a vascular supply for the viability of solid neoplasms is well documented. Investigation  of this critical component of neoplastic growth with an aim toward therapy was initiated by Folkman and associates in experimental situations almost three decades ago (Folkman et al., 1971). Since that time, and especially during the past few years, a large number of antiangiogenic agents have entered clinical trial, the number being in excess of 30 and exhibiting a variety of mechanisms either directly or indirectly associated with angiogen- esis of neoplasia (Thompson et al., 1999). The directly acting agents, such as angiostatin and endostatin, inhibit endothelial cell proliferation directly (O’Reilly et al., 1997). Other agents are directed toward inhibiting the signal transduction pathway regulated by the vascular endothelial growth factor (VEGF) (Salven et al., 1998; Veikkola  and Alitalo, 1999). Both antibodies  di- rected toward the growth factor and direct antagonists of smaller molecular structure have been utilized in clinical trials (Thompson et al., 1999). In theory, this approach offers great promise, since it does not involve a direct attack on the neoplastic cell itself but rather on host cells that the neoplasm requires for maintenance and growth (Boehm et al., 1997; Gastl et al., 1997). Al- though these agents are not without side effects, it might be anticipated that they are much less toxic than a number of the chemotherapeutic agents in standard use (Thompson et al., 1999), and thus the potential for this type of therapy as primary therapy or as an adjunct to other therapies appears to be very great at the present time.

Gene Therapy of Neoplasia

As our capability for the direct transfer of genetic information  into cells increases, the use of gene therapy in neoplasia has become a realistic potential in modern-day chemotherapy. Trans- fection of a normal tumor suppressor gene that is defective in neoplastic cells, such as the p53 gene (El-Deiry, 1998), would be an obvious target for gene therapy. However, a number of other potentials include the use of gene transfer vectors to provide high concentration  of antiangio- genic proteins within organs (Kong and Crystal, 1998), methods to modify methylation of intro- duced genes (Szyf, 1996), and the specific stimulation of the immune system, thereby enhancing immunity to specific neoplasms in the form of DNA vaccines, as discussed in Chapter 19.

A variety of gene transfer methods affording introduction of specific genes into target cells have been utilized. A number of these methods are listed in Table 20.12. Such gene transfer may

be carried out in cells in vitro, such cells then being administered to the host, or a cell-free direct gene transfer into cells in vivo. When administered in vivo, viral vectors may be used, a number of which have been attempted (cf. Roth and Cristiano, 1997), but DNA in liposomes or some other complex that is readily taken up by cells allowing entrance of the DNA into the nucleus have also been used. Although it is likely that only a few neoplastic cells may take up specific genes in these therapeutic regimens, the “bystander” effect, mediated to a significant degree by connexins (Freeman et al., 1993; Mesnil et al., 1996), may prove an effective mediator of such gene therapies.

As pointed out by Gómez-Navarro et al. (1999), there are a variety of obstacles in cancer therapy for which potential contributions of gene therapy may be effective. A list of these, taken from their recent article, is seen in Table 20.13, which is relatively self-explanatory.  As noted, many of the potential contributions of gene transfer may not be realized until well into the fu- ture; however, with the continuing increase in knowledge and technology, the future for specific gene therapy of neoplasia is bright.

Epilogue

Cancer: Tomorrow and the Future

In the 15 years since the publication of the third edition of this textbook, a veritable explosion of knowledge has occurred in the fields of cell and molecular biology, genetics, computer technol- ogy and bioinformatics, and many other basic and applied fields. Simultaneously, there has been an explosion in our knowledge of neoplasia. This knowledge has possibly led to some concrete results in that the overall death rate from cancer in the United States decreased by 3% during the period 1990–1995  (Cole and Rodu, 1996) and in the European  Union by about 7% between

1988 and 1996 (Levi et al., 2000). However, as was the case 15 years ago, there is still no “magic bullet” to cure cancer, unlike the antibiotics that are able to cure the majority of bacterial infec- tions in the human. Just as it was 15 years ago, despite the explosion in knowledge,  medical science continues to be frustrated in its effort to establish a truly effective therapy for the most common forms of malignant neoplasms in the human, such as lung, breast, prostate, and gas- trointestinal tract. The elusive “answer to cancer” appears to be just over the hill and beyond, despite the many truly striking discoveries that have been made in biology in this past decade and a half.

As in the earlier editions of this text, and at the suggestion of several reviewers, we pro- posed several areas of oncology that might hold promise for a control of this disease. Review of the epilogue to the third edition indicates that progress has been made in the areas suggested at that time: cancer prevention, the natural history of development and the nature of the cancer cell, and the therapy of neoplasia itself. This epilogue is not prophetic, but is more of an update and suggests some directions for investigation that might be taken in the future. They are necessarily biased and thus open to considerable criticism. An old colleague of mine, Dr. Vladimir Shapot of the former Soviet Union, once remarked in a seminar he gave at the McArdle Laboratory, “Each investigator  doing cancer research is completely  convinced  that his or her direction is leading to a better understanding  of the disease and its control.” The truth in this statement is self-evident, since investigators in the field would not be undertaking their studies unless, at least in the back of their minds, they were convinced that their approach was the way to go. If such optimism exists and continues, then we hope one day to control neoplasia.

CANCER  PREVENTION

Just as our knowledge of the nature of the chemical induction of cancer increased dramatically prior to the publication of the third edition of this text, our knowledge and application of such knowledge to the viral causation of neoplasia have increased rapidly in the past 15 years. Even more rapidly, perhaps, has the field of the genetics of cancer development expanded, as well as our understanding of the molecular mechanisms involved in the genetic induction of neoplasia. In fact, much of our present knowledge of the basic molecular nature of the cancer cell itself in comparison with its normal counterpart has developed from these latter two areas. Such infor- mation offers enormous potential in the area of cancer prevention. The vaccine against the hepa- titis B virus is very effective in preventing infection by the virus and, when given early in life, prevents the chronic hepatitis that can so readily result when the infection develops in young children. It is the chronic infection that leads to hepatocellular carcinoma. Vaccines for the pap- illoma virus, which may cause at least as many cases of neoplasia in humans as hepatitis B, are already being tested. A vaccine for the Epstein-Barr virus is also quite feasible, and since viral and other infectious causes of neoplasia are probably associated with 15% or more of all human neoplasms  worldwide,  prevention  by active vaccination  could lead within a few decades to a dramatic decrease in several types of neoplasms  if public health systems were to function at reasonable efficiency in all countries.

It is now possible to determine by molecular technologies  the presence of mutations in specific tumor suppressor genes that lead to heritable neoplasms, but various social requirements for privacy, as well as the fear of individuals that they may carry a defective gene, have not al- lowed us to realize the promise that cancer genetics holds. Perhaps with the elucidation of the DNA sequence of the entire human genome, and with it the identification of the numerous other “modifier” genes that are probably far more important, the genetic mechanisms leading to neo- plasia will be made clear. The use of genetic information to prevent the development of cancer in specific individuals may then be brought closer to fruition.

The “passive”  prevention  of neoplasia  by abstinence  from tobacco use, moderate  con- sumption of alcohol, and healthy dietary practices is beginning to alter in a favorable way both the incidence and the death rate of specific neoplasms such as those of the lung, stomach, and, in some populations, liver. The potential for cancer prevention through such passive means is enor- mous. Epidemiological  studies have shown that smoking, diet, reproductive  mores, infectious agents, alcoholic beverages, and industrial contaminants are factors in more than two-thirds of neoplasias in the human. Almost all the epidemiological studies of the causes of human neopla- sia are supported by numerous scientific investigations in the laboratory. It is hoped that, in the future, a major priority of our society will be the prevention of cancer caused by these various agents through educational, governmental,  and behavioral-modification  modalities. Ultimately, however, cancer prevention must be an individual and societal decision. Hopefully, such deci- sions will be based on solid scientific grounds. Although gerontologists tell us that the elimina- tion of cancer as a disease would increase the expected lifetime of each of us by only a few years, the collective fear of cancer in our society is still reflected in the words of former Univer- sity of Wisconsin President Glenn Frank (quoted on page 1).

THE NATURAL  HISTORY  OF NEOPLASTIC  DEVELOPMENT  AND THE NATURE  OF THE CANCER  CELL

That the natural history of neoplastic development occurs in stages in a multistep manner is vir- tually an accepted fact. In both animals and humans, substantial evidence for the existence of

Epilogue

distinct cell types occurring  in the stages of promotion  and progression  has been elucidated (Chapters 7, 9, and 10). Most of the factors causing the two-thirds of preventable human cancer are promoting agents or have as their major component promoting agents. The action of promot- ing agents may be eliminated by their removal from the environment of the individual or by the simultaneous administration of chemopreventive  agents that will antagonize or completely pre- vent the action of the promoting  agent even if exposure continues.  The majority of so-called “nongenotoxic” carcinogens (Table 9.11) are promoting agents and thus, from our knowledge of the characteristics of promoting agents (Chapter 7), pose a risk to the general population that is significantly different from that from complete carcinogens. Hopefully, future regulatory actions taken by governments in an attempt to reduce the cancer risk of humans exposed to such agents will be based on the distinctive known characteristics of promoting agents rather than on treat- ment of all carcinogens as mechanistically identical.

There have been considerable advances in the methods used to detect the early develop- ment of neoplasia, through a variety of radiological devices such as the CAT scan, nuclear mag- netic resonance, and nuclear medical techniques for identifying and localizing preneoplasia and early neoplasia. Such techniques have already been utilized in the early control and cure of ma- jor human neoplasms such as those of the breast, gastrointestinal tract, and lymphoid system. In the future such technologies  may become almost routine in evaluation of patients at potential risk for the development of neoplasia long before the disease becomes clinically apparent.

It would appear that our basic knowledge of the stage of progression has become both a blessing and a curse with respect to the ultimate control of cancer as a disease. Molecular biol- ogy has allowed us to define and describe numerous molecular changes in neoplastic cells and identify an ever-expanding  number of proto-oncogenes  and tumor suppressor genes as well as many of the basic mechanisms involved in the regulation of cell replication. Although this enor- mous amount of work has described in ever-increasing  detail the molecular characteristics  of neoplastic cells—even to the point of the changes in expression of thousands of genes now mea- sured on “chips” and “gene screens”—the  information derived has still not allowed us a basic understanding of the mechanism of evolving karyotypic instability, the critical characteristic of the stage of progression.  In fact, the latter could be the curse behind the elusiveness  of the “magic bullet” to control cancer after its evolution to successful metastatic spread. If we cannot control the karyotypic evolution of the neoplastic cell by some reasonably selective means, we may not be able to control the disease when it is first apparent to physicians in many cancer patients. The optimistic view of this conundrum is that molecular technologies and knowledge of the neoplastic cell itself will ultimately reveal the mechanistic nature of karyotypic evolution, allowing for a rational therapeutic elimination of all neoplastic disease.

THE FUTURE  OF CANCER  THERAPY

Only two facets of the therapy of neoplasia are considered in this text: chemotherapy and immu- notherapy. However, most students of oncology are vitally interested in—and usually have ac- quired a significant amount of knowledge about—the types of therapy used in the treatment of human cancer. In the past, the principal therapies to treat neoplasia were surgery, radiotherapy, and chemotherapy, as well as, although it has not been highly successful, immunotherapy. Since the publication of the third edition of this text, there have been considerable refinements in ra- diotherapy, chemotherapy, and immunotherapy. Advances in radiotherapy have been concerned primarily with the ability to treat an exact volume of tissue with a specific dose by using a vari- ety of sophisticated instrumentations. In particular, this has led to decreased morbidity and, in a number of instances, to increased therapeutic effectiveness. Several new families of chemothera-

peutic drugs have become available, such as the taxols and topoisomerase inhibitors discussed in Chapter 20. One of the most exciting and potentially effective chemotherapeutic  modalities be- ing extensively  investigated  is the group of chemicals, growth factors, and related agents that prevent the growth or alter or destroy the vasculature  of the growing neoplasm (Chapter 18). Although the efficacy of such agents has been clearly demonstrated only in animal systems thus far, this type of therapy, since it does not attack the neoplastic cell directly and therefore is not influenced by the karyotypic instability of the neoplastic cell, could potentially be a true “magic bullet” against malignant neoplasms.

As emphasized in Chapter 19, the role of immunotherapy  in preventing the development of early neoplasia and in curing advanced neoplasms that have previously been treated by the standard methods of surgery, radiotherapy, or chemotherapy has not yet been realized. With the advances  in vaccine technology,  antigen identification  and characterization,  and immune-cell therapy, immunotherapy should play a greater role both in preventing early disease and in elimi- nating micrometastases and residual neoplasms after “debulking” of the primary neoplasms and major metastases in the patient. However, unlike the attack on the vascular system of the neo- plasm, which is indirect, the direct effect of immunotherapy on the neoplastic cell must still con- tend with karyotypic evolution in the stage of progression.

The induced differentiation  of neoplastic  cells, which has been shown to occur both in vivo and in vitro, has also not yet been successfully used in the therapy of most neoplasms. The induced differentiation of cells of acute promyelocytic leukemia by retinoids (Chapter 6) is the best example of successful differentiation  therapy of neoplasia, although it does not lead to a lasting cure in the human patient. Since a large number of “differentiating  agents” that induce the differentiation  of neoplastic  cells both in vivo and in vitro has been developed  in animal systems, their potential for the treatment of human disease still remains a significant possibility.

As the population  of the world increases, so will the incidence of neoplastic  disease in both the young and the old unless we can apply in much stricter ways our knowledge  of the prevention of neoplasia and develop effective curative therapies for cancer in all age groups. Let us hope that present and future generations will strive to achieve the goals of effective prevention and cure of cancer toward which this text is directed.

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