Tumor stem cell heterogeneity: implications with respect to classification of cancers by chemotherapeutic effect.

Herein we have considered the types of tumor stem cell heterogeneity that might account for (a) fluctuating degrees of response to chemotherapy in similarly treated individuals bearing a particular neoplasm, and (b) classifications of cancers by chemotherapeutic effect. Fluctuating ratios of T/R to T/O stem cells, as predicted by the mutation theory, will account for (a). In different circumstances at least three phenomena might account for (b): growth fraction differences, differences in T/R to T/O stem cell ratios, or differences with respect to pharmacologic sanctuaries. T/R stem cells are primarily responsible for the failure of the best available chemotherapy to cure responsive, refractory, and very refractory experimental neoplasms. The data examined suggest that differences in the T/R to T/O stem cell ratios in different types of cancer may account for their being classed as responsive, refractory, or very refractory. If this be true, what might underlie such differences? The most obvious possibilities are: higher mutation rates to a drug-resistant state in refractory cancers, or some sort of "natural selection" of diverse T/R stem cells in refractory cancers.

Establishment of cross-resistance profiles for new agents.

Sublines of murine leukemias (L1210 and P388) and solid tumors selected for resistance to representatives of all of the chemical and functional classes of clinically useful anticancer drugs have been isolated and established in serial in vivo passage and, in some cases, in vitro culture. Extensive resistance, cross-resistance, and collateral-sensitivity patterns have been established with most of the sublines of the drug-resistant murine leukemias under treatment with greater than 100 different established and clinically useful anticancer drugs or new candidate anticancer drugs currently under study. Patients selected for inclusion in phase I-II trials usually have tumors that have failed to respond to treatment with established clinically useful drugs, either from the start of treatment or during continuing treatment after initial useful response. These treatment failures are no doubt due, in many cases, to drug-resistant tumors if initially unresponsive or to the overgrowth of drug-resistant mutant tumor stem cells in initially responding patients who ultimately failed under continuing treatment. Therefore, the cross-resistance profiles of drug-resistant murine tumors to treatment with new drugs going into phase I-II trials should provide useful guides for patient selection for those trials. Also, these cross-resistance profiles will provide useful information indicating likely biochemical mechanism of action of new drugs with promising anticancer activity, thus guiding drug selection for combination chemotherapy trials in animals or man. Numerous examples of all of the above indications for useful application of such information derived from chemotherapy trials with drug-resistant murine tumors are reported.

Stepwise progress in the treatment of disseminated cancers.

Remarkable progress has been made in curing a significant number of disseminated cancers, but at times the pace has seemed discouragingly slow. When I look back at both the successes and failures, and relate them to current concepts, I cannot help but wonder if the rate of future progress might be accelerated by application of basic tenets of the 40-year-old somatic mutation theory. By this I mean serious consideration of the implications of this theory in interpretation of available data and in the design of future therapeutic regimens.

Adjuvant chemotherapy.

In this brief presentation, an attempt was made to illustrate why it is not possible to carry over chemotherapeutic trial results from one animal cancer to another or one human cancer to another without corrections for differences in (a) staging, (b) dose response, and (c) tumor regrowth rates. Interrelation of quantitative information on these same three variables has provided useful guidance in the planning and interpretation of experimental therapeutic trials. For example, such integration analyses show that selection and overgrowth of specifically and permanently drug-resistant tumor cells is a major cause of chemotherapeutic failure in cancers that initia-ly respond. Surgery followed by optimum chemotherapy improves the "cure rate" of all metastatic solid animal cancers that have been studied to date. However, surgery followed by chemotherapy fails in those animals in which the residual tumor cell burden (after surgery) is too large for the chemotherapy now available.