Combination versus single agent chemotherapy: A review of the basis for selection of drug treatment of cancer

DeVita, Vincent T.; Young, Robert C.; Canellos, George P.

doi:10.1002/1097-0142(197501)35:1<98::aid-cncr2820350115>3.0.co;2-b

Cited by 370 publications

(185 citation statements)

References 32 publications

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“…Combination therapy plays a significant role in pharmacotherapy (1). One important aspect of combination therapy is the potential for synergistic effects.…”

Section: Introductionmentioning

confidence: 99%

Tumor Static Concentration Curves in Combination Therapy

Cardilin

Almquist

Jirstrand

et al. 2016

AAPS J

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Abstract.Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h −1 and the natural cell death to 0.0039 h −1 resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound. When the compounds are given as single-agents, the required concentrations were computed to be 506 μg · mL −1 and 56 ng · mL −1 for cetuximab and cisplatin, respectively. A TSC curve is constructed for different combinations of the two drugs, which separates concentration combinations into regions of tumor shrinkage and tumor growth. The more concave the TSC curve is, the lower is the total exposure to test compounds necessary to achieve tumor regression. The TSC curve for cetuximab and cisplatin showed weak concavity. TSC values and TSC curves were estimated that predict tumor regression for 95% of the population by taking between-subject variability into account. The TSC concept is further discussed for different concentration-effect relationships and for combinations of three or more compounds.

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“…Combination therapy plays a significant role in pharmacotherapy (1). One important aspect of combination therapy is the potential for synergistic effects.…”

Section: Introductionmentioning

confidence: 99%

Tumor Static Concentration Curves in Combination Therapy

Cardilin

Almquist

Jirstrand

et al. 2016

AAPS J

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“…17 Complete responses were rare. Although it may be possible that response rates for cyclophosphamide may be slightly higher than the rate of 27% reported from early trials, it is extremely unlikely that the partial and complete response rates observed in our patient population could be obtained by cyclophosphamide alone.…”

Section: Discussionmentioning

confidence: 99%

Positive response to neoadjuvant cyclophosphamide and doxorubicin in topoisomerase II nonamplified/HER2/neu negative/polysomy 17 absent breast cancer patients

Malmgren¹,

Kaplan²

2010

CMAR

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Purpose: Human epidermal growth factor receptor 2 (HER2)/neu, topoisomerase II alpha (TOP2A), and polysomy 17 may predict tumor responsiveness to doxorubicin (DOX) therapy. Methods: We identified neoadjuvant DOX/cyclophosphamide treated breast cancer patients in our registry from 1997 to 2008 with sufficient tissue for testing (n = 34). Fluorescence in situ hybridization (FISH) testing was done on deparaffinized tissue sections pretreated using vendor's standard protocol modification, and incubated with US Food and Drug Administration approved Abbott Diagnostics Vysis PathVysion probe set, including Spectrum-Green-conjugated probe to α-satellite DNA located at the centromere of chromosome 17 (17p11.1-q11.1) and a Spectrum-Orange-conjugated probe to the TOP2A gene. Morphometric analysis was performed using a MetaSystems image analysis system. Manual counting was performed on all samples in which autofluorescence and/or artifact prevented the counting of sufficient numbers of cells. A ratio .2.0 was considered positive for TOP2A amplification. Polysomy 17 (PS17) presence was defined as signals of $2.5. Outcomes were pathological complete response (pCR), partial response (PR), and nonresponse (NR).Results: Of 34 patients tested, one was TOP2A amplified (hormone receptor negative/HER2 negative, partial responder). The subset of TOP2A nonamplified, HER2 negative, and PS17 absent (n = 23) patients had treatment response: pCR = 2 (9%), PR = 14 (61%), and NR = 7 (30%). Including the two PS17 present and HER2-positive patients (n = 33), 76% of TOP2A nonamplified patients had pCR or PR. Conclusions: We observed substantial treatment response in patients lacking three postulated predictors that would be difficult to attribute to cyclophosphamide alone. Patients who are HER2 negative and lack TOP2A amplification and PS17 should not be excluded from receiving DOX-containing regimens.

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“…It is becoming increasingly evident in cancer treatment that simultaneously targeting multiple critical pathways using combinations of chemotherapeutic drugs can enhance outcomes (14)(15)(16)(17). Conventional screening of chemotherapeutics uses an established panel of cancer cell lines (18) that have been derived from bulk tumors.…”

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confidence: 99%

Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

Carstens

Fisher

Acharya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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A new paradigm in oncology establishes a spectrum of tumorigenic potential across the heterogeneous phenotypes within a tumor. The cancer stem cell hypothesis postulates that a minute fraction of cells within a tumor, termed cancer stem cells (CSCs), have a tumor-initiating capacity that propels tumor growth. An application of this discovery is to target this critical cell population using chemotherapy; however, the process of isolating these cells is arduous, and the rarity of CSCs makes it difficult to test potential drug candidates in a robust fashion, particularly for individual patients. To address the challenge of screening drug libraries on patient-derived populations of rare cells, such as CSCs, we have developed a drug-eluting microarray, a miniaturized platform onto which a minimal quantity of cells can adhere and be exposed to unique treatment conditions. Hundreds of drug-loaded polymer islands acting as drug depots colocalized with adherent cells are surrounded by a nonfouling background, creating isolated culture environments on a solid substrate. Significant results can be obtained by testing <6% of the cells required for a typical 96-well plate. Reliability was demonstrated by an average coefficient of variation of 14% between all of the microarrays and 13% between identical conditions within a single microarray. Using the drug-eluting array, colorectal CSCs isolated from two patients exhibited unique responses to drug combinations when cultured on the drug-eluting microarray, highlighting the potential as a prognostic tool to identify personalized chemotherapeutic regimens targeting CSCs.personalized medicine | chemopredictive | cancer stem cell | microarray | combination therapy

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Combination versus single agent chemotherapy: A review of the basis for selection of drug treatment of cancer

Cited by 370 publications

References 32 publications

Tumor Static Concentration Curves in Combination Therapy

Tumor Static Concentration Curves in Combination Therapy

Positive response to neoadjuvant cyclophosphamide and doxorubicin in topoisomerase II nonamplified/HER2/neu negative/polysomy 17 absent breast cancer patients

Drug-eluting microarrays to identify effective chemotherapeutic combinations targeting patient-derived cancer stem cells

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