Lung Cancer Resistance to Chemotherapy

Stewart, David J.

doi:10.1007/978-1-60761-524-8_15

Cited by 1 publication

(2 citation statements)

References 338 publications

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“…The reasons for this incurability are unknown. Several resistance mechanisms have been described in SCLC cell lines and xenografts8, 60, but it is unclear which of these are important clinically. While this study was limited by a relatively small number of evaluable studies and by our inability to correct for the contribution of concurrent agents in drug combination studies, the lack of a statistically significant association between dose intensity of any agent and estimated cell kill would argue against a steep DRC for any of the agents assessed.…”

Section: Discussionmentioning

confidence: 99%

“…In both preclinical and clinical studies, numerous resistance mechanisms have been noted in SCLC8, 60, and it remains unknown which ones are most important clinically. The field would benefit from carefully done translational studies (with tumor biopsies prior to therapy initiation and again at the time of maximum response and at the time of relapse) to assess how tumor cell growth characteristics, resistance factors, and factors required for therapy efficacy (eg, drug obligate targets, drug transporters, drug activators, and proapoptotic factors) change over the course of therapy.…”

Section: Discussionmentioning

confidence: 99%

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Extensive Disease Small Cell Lung Cancer Dose-Response Relationships: Implications for Resistance Mechanisms

Johnson

López

Glisson³

et al. 2010

Journal of Thoracic Oncology

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Background Some studies (but not others) suggested high doses are beneficial in small cell lung cancer (SCLC). We hypothesized dose-response curve (DRC) shape reflects resistance mechanisms. Methods We reviewed published SCLC clinical trialss and converted response rates into estimated mean tumor cell kill, assuming killing is proportional to reduction in tumor volume. Mean % cell survival was plotted vs planned dose-intensity. Nonlinear and linear meta-regression analyses (weighted according to the number of patients in each study) were used to assess DRC characteristics. Results Although associations between dose and cell survival were not statistically significant, DRCs sloped downward for 5 of 7 agents across all doses and for all 7 when lowest doses were excluded. Maximum mean cell kill across all drugs and doses was approximately 90%, suggesting there may be a maximum achievable tumor cell kill irrespective of number of agents or drug doses. Conclusions Downward DRC slopes suggest that maintaining relatively high doses may possibly maximize palliation, although the associations between dose and slope did not achieve statistical significance, and slopes for most drugs tended to be shallow. DRC flattening at higher doses would preclude cure, and would suggest that “saturable passive resistance” (deficiency of factors required for cell killing) limits maximum achievable cell kill. An example of factors that could flatten the dose-response curve at higher doses and lead to saturable passive resistance would be presence of quiescent, non-cycling cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%