Why does cytotoxic chemotherapy cure only some cancers?

Abstract

Despite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors. By contrast, in testicular cancer, gestational choriocarcinoma, Hodgkin disease and high-grade lymphomas, chemotherapy is routinely curative, even for patients who present with widely disseminated disease. In the common advanced cancers, however, over 40 years of cytotoxic drug development has brought no significant change in cure rates. One interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. We suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells. A common property of such curable malignancies is that they arise from cells that undergo major genetic rearrangements or recombination as part of their normal physiology. The absence of further genetic and epigenetic changes in genes that regulate apoptosis, DNA repair and senescence allows these cells to maintain their intrinsic sensitivity to chemotherapy. This process allows the cells, when challenged with chemotherapy, to undergo the natural apoptotic pathways that contribute to their intrinsic qualities of chemosensitivity and high curability.

Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, with potential anti-tumor activity against apoptosis-resistant cancer cells

“…Savage and colleagues (1) report that one interpretation is that the intrinsic properties of the malignancies themselves, rather than the qualities of individual drugs or combination therapies, are primarily responsible for their curability with chemotherapy. These authors thus suggest that the curability of these malignancies results from an intrinsic 'locked-in' state of sensitivity to proapoptotic stresses in these cells (1). In fact, >90% of cancer patients die from their metastases (2).…”

“…Despite frequent responses to chemotherapy, curative treatment remains elusive for the majority of patients with metastatic solid tumors (1). Indeed, in the common advanced cancers, over 40 years of cytotoxic drug development has brought no significant change in cure rates (1).…”

“…In fact, >90% of cancer patients die from their metastases (2). Drug resistance, either acquired or intrinsic, often prevents tumor cells from undergoing sufficient levels of apoptosis, resulting in cancer cell survival and treatment failure (1,2). The metastatic process is inherent to a significant level of resistance to apoptosis.…”

Loss-of-function genetic screens as a tool to improve the diagnosis and treatment of cancer

“…Multiple mechanisms have been suggested for the resistance of cancer cells to conventional chemotherapy, for example, the upregulation of drug pumps and (in)-activation of pathways on which the drug works (Gottesman et al, 2002;Rodriguez-Antona and Ingelman-Sundberg, 2006;Savage et al, 2009). However, in most cases, the factors that contribute to drug resistance are not known and RNAi screens can be useful to identify genes that modulate drug responses.…”

Phenotype heterogeneity in cancer cell populations

“…The importance of drug-induced drug resistance in cancer cell populations has long been recognised in the clinic, its molecular mechanisms partially identified in vitro, and mathematical models proposed to account for it and predict it [1]. Undisputable cures have been obtained in some occurrences by targeted therapies when a unique target exists and a specified molecule has been identified, able to successfully inhibit it (imatinib in chronic myelogenous leukaemia or all-transretinoic acid in acute promyelocytic leukaemia), or by combinations of cytotoxic drug in cases of solid tumours with intact p53 [2]. However, most cancers, after initial shrinkage of tumour mass and temporary remission due to chemotherapy, with variable delays relapse and eventually escape all therapies.…”