Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: a hypothesis

Abstract

With chemotherapy, the in vitro and clinical dose-response curve is steep in some situations, but is relatively flat in others, possibly due to the mechanism by which tumors are resistant to chemotherapy. For tumors with resistance due to factors that actively decrease chemotherapy efficacy (e.g., p-glycoprotein, glutathione, etc.), one would predict that high dose chemotherapy and therapy with some resistance modulating agents would increase therapeutic efficacy. Such "active" resistance would most likely generally arise from gene amplification or over expression, and would be characterized by a shoulder on the log response vs. dose curve, with eventual saturation of the protective mechanism. On the other hand, one would expect that high dose chemotherapy and most resistance modulating agents would be of little value for tumors with resistance due to defective apoptosis or due to a deficiency in or decreased drug affinity for a drug target, drug activating enzyme, drug active uptake system, or essential cofactor. Such "passive" resistance would most likely generally arise from gene down regulation, deletion, or mutation, and would probably be characterized by a relatively flat log response vs. dose curve, or by a curve in which a steep initial section is followed by a plateau, as target, etc., is saturated. (If response were plotted vs. log dose, then compared to the curve for a sensitive cell line, the curve for active resistance would be analogous to the pharmacodynamic curve seen with competitive antagonism [i.e., a sigmoid curve shifted to the right], and the curve for most types of passive resistance would be analogous to the pharmacodynamic curve seen with noncompetitive antagonism [i.e., a sigmoid curve with reduced maximal efficacy]. As such, one might also refer to active vs. passive resistance as competitive vs. noncompetitive resistance, respectively.) Many tumor types probably possess a combination of active and passive mechanisms of resistance. New in vivo strategies could be helpful in defining dose-response relationships, mechanisms of resistance, and targets for resistance modulation. Such in vivo studies would be conducted initially in animals, but might also be tested clinically if animal studies demonstrated them to be feasible and useful. These in vivo studies would be conducted by randomizing 5-25 subjects to one of 10-20 dose levels over a potentially useful therapeutic range. Nonlinear regression analysis would then be used to define the characteristics of a curve generated by plotting against dose the log percent tumor remaining after the first course of therapy. While this might offer insight into the nature of resistance mechanisms present initially, plotting further tumor shrinkage vs. dose-intensity vs. course number for each later treatment course (or plotting dose-intensity vs. time to tumor progression) might provide information on how tumors become increasingly resistant to drugs following treatment.

Phase II study of alternating chemotherapy regimens for advanced non-small cell lung cancer

“…Based on these analyses, we felt that clinical activity of most chemotherapy agents against non-small cell lung cancer was limited by saturable or non-saturable passive resistance, rather than by active resistance when used as single agents [8][9][10][11][12][13][14][15], and by saturable passive resistance when used in two-drug combinations [15]. By our theory, the best strategy against saturable passive resistance would be the combined use of agents with differing mechanisms of action [7], and the use of combination chemotherapy has arguably proven to be the best anti-resistance strategy tested to date. To test these concepts, we conducted a phase II non-small cell lung cancer study in which agents with differing mechanisms of action were alternated with one another.…”

“…It is unclear why non-small cell lung cancer is relatively resistant to chemotherapy. We proposed that resistance mechanisms be classified as ''active'' or ''passive'' [7], and passive resistance could be further subdivided into ''saturable passive'' or ''non-saturable passive'' resistance. Active resistance is due to excess of a factor (e.g.…”

A phase II study of sequential docetaxel and gemcitabine followed by docetaxel and carboplatin as first-line therapy for non-small cell lung cancer

“…The first one appears due to a factor deficiency while the second one appears due to a factor mutation or alteration [5]. Based on several analyses, Stewart et al postulated that non-saturable passive resistance lead single-agent regimens to clinical limitations while two-drug combinations had resulted in limited clinical efficacy due to saturable passive resistance [5]. Theoretically, the best way to overcome these limitations is the introduction of chemotherapeutic agents with different mechanisms of action.…”

“…Generally, two types of resistance are known: the active resistance which could be translated into the competitive inhibition of drug effect, and the passive resistance subdivided into saturable and non-saturable passive resistance. The first one appears due to a factor deficiency while the second one appears due to a factor mutation or alteration [5]. Based on several analyses, Stewart et al postulated that non-saturable passive resistance lead single-agent regimens to clinical limitations while two-drug combinations had resulted in limited clinical efficacy due to saturable passive resistance [5].…”

Re: Design of Phase II Cancer Trials Using a Continuous Endpoint of Change in Tumor Size: Application to a Study of Sorafenib and Erlotinib in Non-Small Cell Lung Cancer

“…We agree with them as to the value of reporting response as a continuous variable and would like to suggest some additional possible uses of this approach. We have proposed that plotting percent change in tumor size versus treatment dose might offer increased insight into dose -response relationships and that this might be used to infer predominant resistance mechanisms ( 2 ). Furthermore, the relationship of change in tumor size versus dose with the first cycle of therapy may reflect intrinsic resistance mechanisms, whereas the relationship to dose of further change in tumor size with later cycles of therapy may suggest how acquired resistance differs from intrinsic resistance ( 2 ).…”