Serum and tissue concentrations of doxorubicin after IV administration of doxorubicin or doxorubicin-DNA complex to patients with gastrointestinal cancer

Gunvén, Peter; Theve, Nils Olof; Peterson, Curt

doi:10.1007/bf00306745

Cited by 22 publications

(9 citation statements)

References 13 publications

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“…Senescence is important for in situ radio-sensitization of human prostate cancer cells [44], and mice bearing tumors developing drug-induced senescence have enhanced prognosis following chemotherapy as compared to those harboring tumors with defective senescence mechanisms [45]. The clinical doses of doxorubicin (0.13 to 1.5 nmol/g) [46] were found to cause senescence in vitro [32], suggesting a role for senescence in regulating doxorubicin efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…As we observed enhanced drug-induced senescence both in vitro and in vivo , we reasoned that senescence may be a major cell arrest pathway involved. Although clinical doses of doxorubicin cause senescence in vitro [32], [46], the true effect of low doses of doxorubicin requires further in vivo study. In conclusion, these results demonstrate that PTTG1 regulates drug-induced senescence, providing new insights for the role of PTTG1 in determining cancer cell responses to anti-neoplastic treatments.…”

Section: Discussionmentioning

confidence: 99%

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PTTG1 Attenuates Drug-Induced Cellular Senescence

et al. 2011

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As PTTG1 (pituitary tumor transforming gene) abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1−/−) exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1−/− senescent cells increased ∼4 fold as compared to WT PTTG1-replete cells (p<0.001). p21, an important regulator of cell senescence, was induced ∼3 fold in HCT116 PTTG1−/− cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1−/− cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1−/− HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1−/− tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PTTG1 Attenuates Drug-Induced Cellular Senescence

et al. 2011

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“…3 and 4, based on the optimized parameters in mice (Table I), the predicted median concentrations and variable ranges close to the observation in plasma and tissues in rats and humans. Dose-normalized doxorubicin concentrations in human breast, carcinoid, liver, and omental tumors were digitized from the literature and compared with our model predictions (32, 33). In general, our developed model, using xenograft data, roughly predicted doxorubicin concentrations in human tumors.…”

Section: Resultsmentioning

confidence: 99%

A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts

Liu

et al. 2018

Pharm Res

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“…27 We sought to mimic a sequential therapy at concentrations which more closely approach achievable therapeutic plasma concentrations in patients. [28][29][30] We identified lower doses of doxorubicin in which cells recovered following cessation of treatment for 48hr. Cells treated with 5-10 nM doxorubicin exhibited minimal changes to overall viability and maintained proliferative capacity compared to higher doses ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

et al. 2016

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Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/ adjuvant chemotherapy. To better understand the growth advantage of TNBC -in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens -by altering signaling pathways critical to cellular survival.

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Serum and tissue concentrations of doxorubicin after IV administration of doxorubicin or doxorubicin-DNA complex to patients with gastrointestinal cancer

Cited by 22 publications

References 13 publications

PTTG1 Attenuates Drug-Induced Cellular Senescence

PTTG1 Attenuates Drug-Induced Cellular Senescence

A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

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