Sir,
We read with great interest the Viewpoint by Seruga and Tannock, published in the October issue of Nature Clinical Practice Oncology.1 There is compelling clinical evidence for the superiority, or at least non-inferiority, of intermittent androgen deprivation (AD) therapy versus continuous AD in prostate cancer. We would like to add that basic research data also support and provide an understanding of the importance of introducing breaks in the hormonal treatment of prostate cancer. Chuu et al. have shown that prostate cancer cell lines could reverse their androgen-independent phenotype to an androgen-stimulated phenotype in mice bearing xenograft tumors.2 Briefly, athymic mice were subcutaneously inoculated with androgen-independent human prostate cancer cells, obtained after long-term AD, and subsequently treated with testosterone. Such treatment resulted in important tumor regression and after 5–6 weeks of therapy, tumor growth resumed in the presence of testosterone. Interestingly, the removal of androgen stopped the growth of these testosterone-adapted tumors, suggesting that AD therapy followed by androgen treatment could maintain prostate tumors in an androgen-dependent state. The concept of intermittent AD therapy assumes recovery of endogenous testosterone levels during break periods, thus prolonging tumor response to further androgen blockade.
Chuu et al. postulated at the time that these findings could also be applicable to other cancer types. Indeed, Sabnis et al. have recently shown that stopping treatment with letrozole could reverse acquired resistance to this aromatase inhibitor in a mouse model of hormone-dependent breast cancer.3 Thus, after discontinuing letrozole treatment for 6 weeks, the administration of the same drug resulted in marked regression of long-term letrozole-treated tumors. In addition it is now clear that, in breast cancer, anti-hormone drug resistance can transform some hormone responsive cells into hypersensitive cells, opening doors for new therapeutic strategies.4
In most cases, incubation with anticancer drugs for a long period of time can lead to acquired drug resistance. Sometimes, if incubation is maintained for long enough, drug dependence can arise. For example, most of the microtubule-targeting agents, such as taxanes,5,6 vinca-alkaloids,7 or epothilones,8 can induce drug dependence at least in vitro. Interestingly, upon withdrawal of the anticancer agent, dependent cancer cells can undergo drug starvation, resulting in growth inhibition and ultimately induction of cell death.5 In addition, dependent cells might become hypersensitive to drugs exerting an opposite effect. For instance, Chinese hamster ovary cells dependent on paclitaxel for their normal growth displayed increased sensitivity to microtubule-depolymerizing drugs, such as colcemid and griseofulvin.9 Similarly, prostate cancer cells acquiring resistance to AD therapy and breast cancer cells resistant to anti-hormone therapy can become hypersensitive and be destroyed by androgen and estrogen, respectively.2,4
Thus, a process that we call the drug-driven dependency deprivation effect might explain the interest in introducing breaks in patients receiving long-term anticancer treatments. During prolonged exposure to anticancer drugs, some cancer cells can become drug-dependent and upon removal of the drug during break periods, their growth can be significantly inhibited and cell death can occur. This effect might not be sufficient to induce tumor regression as observed by Sabnis et al.3 however, the drug-driven dependency deprivation effect might be able to inhibit and destroy the most resistant or dependent cancer clones so that re-induction of sensitivity is observed. Moreover, the drug-driven dependency deprivation effect could explain how the introduction of breaks can prolong tumor response to long-term treatments.
Further investigations, both at pre-clinical and clinical level, are mandatory to characterize this process and decipher the different cellular and molecular pathways involved. If confirmed, the drug-driven dependency deprivation effect could represent a powerful tool for cancer therapy. By introducing breaks in long-term therapies — such as androgen blockade or metronomic chemotherapy –anticancer effects could be obtained during both on- and off-treatment periods, thus potentially increasing treatment efficacy while considerably improving the quality of life of cancer patients.
References
Segura S and Tannock IA (2008) Intermittent androgen blockade should be regarded as standard therapy in prostate cancer. Nat Clin Pract Oncol 5: 574–576
Chuu CP et al. (2005) Androgen causes growth suppression and reversion of androgen-independent prostate cancer xenografts to an androgen stimulated phenotype in athymic mice. Cancer Res 65: 2082–2084
Sabnis GJ et al. (2008) Stopping treatment can reverse acquired resistance to letrozole. Cancer Res 68: 4518–4524
Jordan VG (2008) The 38th David A. Karnofsky lecture: the paradoxical actions of estrogen in breast cancer – Survival or death? J Clin Oncol 26: 3073–3082
Schibler MJ and Cabral F (1986) Taxol-dependent mutants of Chinese Hamster Ovary cells with alterations in α- and β-tubulin J Cell Biol 102: 1522–1531
Kavallaris M et al. (1997) Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific β-tubulin isotypes. J Clin Invest 100: 1282–1293
Slater LM et al. (1992) Novel nucleolar and nuclear morphology in a vincristine-dependent human leukemia cell line (L100). Exp Cell Res 198: 170–174
Yang CP et al. (2005) A Higly resistant epothilone B resistant A549 cell line with mutations in tubulin that confer drug dependence. Mol Cancer Ther 4: 987–995
Cabral F (1983) Isolation of Chinese Hamster Ovary cell mutants requiring the continuous presence of taxol for cell divison. J Cell Biol 97: 22–29
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André, N., Pasquier, E. Response to 'Intermittent androgen blockade should be regarded as standard therapy in prostate cancer'. Nat Rev Clin Oncol 6, E1 (2009). https://doi.org/10.1038/ncponc1317
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DOI: https://doi.org/10.1038/ncponc1317
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