Tumor heterogeneity and drug resistance.

Abstract

Drug resistance has long been identified as a major reason for therapy failure in cancer patients. Concurrently, work from many laboratories in the past 10 years has established tumor heterogeneity as a phenomenon of critical importance in the natural history of individual neoplasms. The two most sinister aspects of intraneoplastic diversity in human solid tumors are the genesis of clones with metastatic potential, and the existence of drug-resistant variants in primary cancers and their metastases. Thus, recent investigations on drug resistance and on tumor heterogeneity have converged to focus attention on the clonal organization of primary tumors and their metastases as the underlying basis for anticancer drug resistance. This review examines the degree of heterogeneity observed within tumors and the relationship of this diversity to resistance that might be anticipated for any given agent. A question critical to our discussion is "How many subpopulations are there?" The impact of multiple tumor clones on therapy is next discussed in relationship to normal tissue tolerance, the barrier clinicians face regardless of the specific agent used in treatment. Finally, laboratory and clinical approaches are presented for addressing a drug resistance problem that is seemingly overwhelming because of its complex biological roots.

Selection of a subpopulation with fewer DNA topoisomerase II alpha gene copies in a doxorubicin-resistant cell line panel

“…It was found that with increasing DOX resistance the population composition gradually changes from a population in which most cells contain three Topolla gene copies to a population in which most cells contain only two copies. This change is in agreement with the hypothesis that during resistance development in human tumours, the resistant cells are initially sporadically present in a genetically heterogeneous tumour, and selected by drug exposure (Dexter and Leith, 1986 (Keith et al, 1993;Murphy et al, 1995). Thus other genes on the same chromosome might be essential for the selection procedure as well.…”

Influence of a haematoporphyrin derivative on the protoporphyrin IX synthesis and photodynamic effect after 5-aminolaevulinic acid sensitization in human colon carcinoma cells

“…The clinical and pharmacological use of combination chemotherapy has been widely studied in animal models (Dexter et al, 1986). The combination of antineoplastic drugs has several advantages over single drug treatment: (1) increasing therapeutic synergism by exploiting different mechanisms of action; (2) increasing patient tolerance by minimizing side-effects of drugs owing to lower doses of each individual compound; and (3) preventing or delaying the emergence of resistant cell clones.…”

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

“…It has long been recognized that tumors are heterogeneous and comprise multiple subpopulations that likely provide a survival and growth advantage for primary tumors and their metastases (65)(66)(67)(68). Tumor cell heterogeneity confounds our understanding of tumor progression, relapse, and therapy (3,7,69).…”