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Biomedical subjects

Herbert M Pinedo

Publications and source records attributed to Herbert M Pinedo.

At least 19 recordsLinked to original sources
PubMed2006

A CD34(+) human cell line model of myeloid dendritic cell differentiation: evidence for a CD14(+)CD11b(+) Langerhans cell precursor.

The study of early events in dendritic cell (DC) differentiation is hampered by the lack of homogeneous primary cell systems that allow the study of cytokine-driven, transitional DC differentiation steps. The CD34(+) acute myeloid leukemia cell line MUTZ-3 displays a unique ability to differentiate into interstitial DC (IDC) and Langerhans cells (LC) in a cytokine-dependent manner. Phenotypic characterization revealed MUTZ-3 to consist of three distinct subpopulations. Small CD34(+)CD14(-)CD11b(-) progenitors constitute the proliferative compartment of the cell line with the ability to differentiate through a CD34(-)CD14(-)CD11b(+) stage to ultimately give rise to a morphologically large, nonproliferating CD14(+)CD11b(hi) progeny. These CD14(+)CD11b(hi) cells were identified as common, immediate myeloid DC precursors with the ability to differentiate into LC and IDC, exhibiting characteristic and mutually exclusive expression of Langerin and DC-specific ICAM-grabbing nonintegrin, respectively. The identity of the MUTZ-3-derived LC subset was confirmed further by the presence of Birbeck granules. We conclude that the MUTZ-3 cell line provides a ready and continuous supply of common myeloid precursors, which should facilitate further study of the ontogeny of myeloid DC lineages.

Antigens, CD↗
PubMed2006

A postmigrational switch among skin-derived dendritic cells to a macrophage-like phenotype is predetermined by the intracutaneous cytokine balance.

Migration of dendritic cells (DC) to secondary lymphoid organs under proinflammatory conditions coincides with their maturation and acquisition of T cell stimulatory abilities. In contrast, impaired activation of DC, e.g., in tumor-conditioned environments, may hamper their activation and possibly their subsequent migration to lymph nodes, leading to either immunological tolerance or ignorance, respectively. In this study, the influence of cytokines in the peripheral skin microenvironment on the activation state of migrating cutaneous DC was assessed using an ex vivo human skin explant model. We observed a phenotypic shift from mature CD83(+) DC to immature CD14(+) macrophage-like cells within 7 days subsequent to migration from unconditioned skin. These macrophage-like cells displayed a poor T cell stimulatory ability and lacked expression of CCR7, thus precluding their migration to paracortical T cell areas in the lymph nodes. The balance of suppressive and stimulatory cytokines during the initiation of migration decided the postmigrational fate of DC with IL-10 accelerating and GM-CSF and IL-4 preventing the phenotypic switch, which proved irreversible once established. These observations indicate that, in immunosuppressed environments, a postmigrational DC-to-macrophage shift may hinder T cell activation, but also that it may be prevented by prior conditioning of the tissue microenvironment by GM-CSF and/or IL-4.

Biomarkers↗
PubMed2006

On our way to targeted therapy for cachexia in cancer?

PURPOSE OF REVIEW: Cachexia, the occurrence of involuntary weight loss due to loss of adipose tissue and skeletal muscle mass, is among the most common and devastating symptoms in patients with advanced cancer. It is a significant factor contributing to the poor performance status and high mortality rate of these patients, and is a distressing problem for both patients and their families. Despite extensive research in an attempt to better understand the mechanisms involved, progress in the management of cancer cachexia has been slow. RECENT FINDINGS: The pathogenic mechanisms of cachexia and anorexia are multifactorial, but cytokines and tumour-derived factors are known to play a significant role, thereby representing suitable therapeutic targets. Moreover, recent advances in the field of molecular biology have shed light on other mediators involved in the mechanisms leading to muscle wasting, thus increasing potential targets for new therapies. SUMMARY: This review will focus on recent findings in relation to the molecular pathways leading to muscle wasting that have improved our current understanding of cachexia and will direct the future management of cachexia in cancer towards targeted therapies.

Antineoplastic Agents↗
PubMed2006

Effects of gemcitabine on cis-platinum-DNA adduct formation and repair in a panel of gemcitabine and cisplatin-sensitive or -resistant human ovarian cancer cell lines.

Gemcitabine (dFdC) can increase the sensitivity of both cisplatin (CDDP)-sensitive and -resistant cell lines. It has been postulated that both formation and repair of platinum-(Pt)-DNA adducts are related to these effects. Therefore, we investigated the effects of dFdC on the formation and repair of Pt-DNA adducts in the human ovarian cancer cell line, A2780, and its CDDP- or dFdC-resistant variants, ADDP and AG6000, which have a different expression of various repair enzymes. Cells were exposed for 1 h to CDDP alone or combined with dFdC in IC50 concentrations, followed by a 1-h exposure to thiourea and, subsequently, by a drug-free period of 1, 3 or 23 h (i.e. 2, 4 or 24 h after CDPP +/- dFdC removal). Pt-DNA adducts were quantified with 32P-post-labeling. The gene expression of the repair enzymes, XPA and XRCC1, was the same in all 3 cell lines but ERCC1, ERCC3 and XPC were 2-6 times higher in AG6000 compared to A2780 cells. In contrast, both ERCC1 and ERCC3 were 10- and 1.5-fold lower in ADDP cells compared to A2780. The mismatch enzyme, MLH1, was lower in ADDP cells. At equally toxic CDDP concentrations, all cell lines formed comparable peak levels of total Pt-DNA adducts (36-48 fmol/microg DNA). However, the time at which peak levels were reached showed large variation. The repair of the adducts was very efficient in the resistant cell lines whereas, in A2780 cells, plateau levels were retained until 24 h after CDDP exposure. In A2780 cells, dFdC shifted the adduct peaks from 4 h to directly after CDDP exposure and increased peak levels by >3.9-fold. dFdC also enhanced the repair of adducts by >1.7-fold and increased the Pt-GG:Pt-AG ratio compared to CDDP alone by >1.4-fold. Overall, dFdC decreased the area under the Pt-DNA adduct-time curve (AUA0-25 h) in A2780 cells by 2.7-fold. In ADDP cells, dFdC shifted the adduct peaks from 2 to 4 h and increased them by >2.2-fold. dFdC also increased the Pt-GG:Pt-AG ratio during the repair process by 1.4-fold. Overall, dFdC increased the AUA0-25 h in ADDP cells by 1.7-fold. In AG6000 cells, dFdC increased the Pt-GG:Pt-AG ratio by 1.6-fold directly after exposure but did not clearly affect the AUA0-25 h. In conclusion, dFdC can affect both Pt-DNA adduct formation and repair, depending on the initial sensitivity of the cells.

Antimetabolites, Antineoplastic↗
PubMed2005

Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies.

PURPOSE: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT. We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food. PATIENTS AND METHODS: Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 thrice daily. Pharmacokinetics was done on days 1, 28, and 56. RESULTS: Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and C(max) (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples. CONCLUSIONS: The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.

Administration, Oral↗
PubMed2005

Induction of p53 up-regulated modulator of apoptosis messenger RNA by chemotherapeutic treatment of locally advanced breast cancer.

PURPOSE: In biopsies of patients with locally advanced breast cancer, we investigated the in vivo changes of the gene expression pattern induced by chemotherapy to find genes that are potentially responsible for the efficacy of the drug. EXPERIMENTAL DESIGN: Early cellular responses to chemotherapy-induced damage, both in vivo and in vitro, were investigated by analyzing chemotherapy-induced changes in gene expression profiles. Core biopsies were taken from nine patients with locally advanced breast cancer, before and at 6 hours after initiation of doxorubicin-based chemotherapy. Both samples were cohybridized on the same microarray containing 18,000 cDNA spots. RESULTS: The analysis revealed marked differences in gene expression profile between treated and untreated samples. The gene which was most frequently found to be differentially expressed was p53 up-regulated modulator of apoptosis (PUMA). This gene was up-regulated in eight of nine patients with an average factor of 1.80 (range, 1.36-2.73). In vitro MCF-7 breast cancer cells exposed to clinically achievable doxorubicin concentrations for 6 hours revealed marked induction of PUMA mRNA, as well. CONCLUSIONS: This is the first report describing PUMA mRNA to be up-regulated as a response to chemotherapy in patients. Because PUMA is a known member of the family of BH3-only proapoptotic proteins, this finding suggests PUMA's potential importance for the response to anticancer drugs.

Adult↗
PubMed2005

Inhibition of angiogenesis in cancer patients.

Treatment with antiangiogenic agents as standard anticancer therapy with or without classical chemotherapy is rapidly approaching. The clinical efficacy of bevacizumab in colorectal cancer in combination with chemotherapy caused a revival of the antiangiogenic strategy. By combining this agent with a tyrosine kinase receptor epidermal growth factor receptor blocker (erlotinib), remarkable responses were seen in renal cell cancer. It has been thought that blocking these biological pathways would cause no drug-related toxicity, but a whole new pattern of relatively mild side effects compared with classical chemotherapy, including skin rash, fatigue and hypertension, has been observed. In combination with chemotherapy, other serious side effects, such as bleeding and thrombosis, also occur. Here, the preclinical and clinical data of antiangiogenic agents in clinical trials at this moment are summarised.

Angiogenesis Inhibitors↗
PubMed2004

A methylester of the glucuronide prodrug DOX-GA3 for improvement of tumor-selective chemotherapy.

The glucuronide prodrug of doxorubicin, DOX-GA3, can be selectively activated in tumors by extracellular human beta-glucuronidase, resulting in a better therapeutic index than doxorubicin. DOX-GA3, however, is rapidly excreted by the kidney. We hypothesized that slow release of DOX-GA3 from its methylester, DOX-mGA3, by esterase activity in blood would result in improved circulation half-life (t(1/2)) of DOX-GA3. DOX-mGA3 was synthesized more efficiently with an overall yield of 60% as compared to 37% in the case of DOX-GA3. We showed that DOX-mGA3 was enzymatically converted to DOX-GA3 with a t(1/2) of approximately 0.5 min in mouse plasma to 2.5 h in human plasma, which was in agreement with differences in esterase activity between species. DOX-mGA3, similar to DOX-GA3, was at least 37-fold less potent than the parent drug doxorubicin in growth inhibition of four different human malignant cell lines in vitro. Incubation of OVCAR-3 cells with DOX-mGA3 in combination with an excess of human beta-glucuronidase (0.05 U mL(-1)) resulted in a similar growth inhibition to that of doxorubicin. Intravenous administration of DOX-mGA3 in FMa-bearing mice resulted in an area under the concentration versus time curve (AUC) of DOX-GA3 in tumor and most normal tissues that was 2.5- to 3-fold higher than after the same dose of DOX-GA3 itself. In tumor tissue, this was accompanied by a 2.7-fold increase in the AUC of doxorubicin from DOX-mGA3 than from DOX-GA3. In conclusion, an advantage of DOX-mGA3 over DOX-GA3 is that this prodrug can be produced with a higher yield. Another important advantage is the improved pharmacokinetics of the lipophilic DOX-mGA3 as compared to that of the hydrophilic DOX-GA3. This effect may even be more pronounced in man, because of the lower plasma esterase activity than measured in mice.

Animals↗
PubMed2004

Sulfasalazine down-regulates the expression of the angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase and interleukin-8 in human monocytic-macrophage THP1 and U937 cells.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) and interleukin-8 (IL-8) are angiogenic factors produced by tumor infiltrating macrophages. Here, we show that prolonged exposure of human monocytic/macrophage THP1 and U937 cells to sulfasalazine, an anti-inflammatory drug and inhibitor of nuclear factor-kappaB (NF-kappaB), resulted in down-regulation of PD-ECGF/TP and IL-8 (mRNA, protein and activity) along with elimination of their induction by tumor necrosis factor-alpha and interferon-gamma. Concomitantly, sulfasalazine-exposed cells were markedly resistant to 5'-deoxyfluorouridine, the last intermediate of capecitabine requiring activation by PD-ECGF/TP. This is the first report suggesting that disruption of NF-kappaB-dependent signaling pathways can provoke a marked and sustained down-regulation of macrophage-related angiogenic factors. However, this may also negatively affect capecitabine efficacy.

Angiogenesis Inducing Agents↗
PubMed2004

The effect of fluoropyrimidines with or without thymidine phosphorylase inhibitor on the expression of thymidine phosphorylase.

Thymidine phosphorylase (platelet-derived-endothelial-cell-growth-factor) catalyzes the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate, activates 5'-deoxy-5-fluorouridine (5'DFUR) and inactivates trifluorothymidine (TFT). The effect of 5'DFUR and TFT with or without a specific thymidine phosphorylase inhibitor (TPI) on thymidine phosphorylase mRNA, protein expression and activity was studied, in three human colon cancer cell lines, WiDR, HT29 and Lovo exposed for 72 h at IC50 concentrations. In Lovo cells TFT plus TPI only increased thymidine phosphorylase-protein expression 1.7-fold; 5'DFUR and TFT treatment increased thymidine phosphorylase mRNA levels 5- and 1.4-fold, respectively. In WiDR cells, 5'DFUR plus TPI significantly decreased thymidine phosphorylase-protein. TFT and TFT plus TPI increased thymidine phosphorylase-protein 2- and 3-fold, respectively. TPI and 5'DFUR decreased thymidine phosphorylase-mRNA levels significantly. In HT29 cells, 5'DFUR and 5'DFUR plus TPI decreased both thymidine phosphorylase-protein and thymidine phosphorylase-mRNA. In all cell lines 5'DFUR and TFT did not affect thymidine phosphorylase activity, but treatment with TPI (alone or in combination) eliminated thymidine phosphorylase activity. This demonstrated that regulation is drug and cell line dependent.

Cell Line, Tumor↗
PubMed2004

18F-2-fluoro-2-deoxy-d-glucose positron emission tomography in staging of locally advanced breast cancer.

PURPOSE: To prospectively evaluate the effect of adding whole-body (18)F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to conventional screening for distant metastases in patients with locally advanced breast cancer (LABC). PATIENTS AND METHODS: All women with LABC referred for participation in the LABC Spinoza trial were considered eligible for this study. Patients were included if chest x-ray, bone scan, liver ultrasound, or computed tomography scan performed by the referring physician failed to reveal distant metastases. They underwent whole-body FDG PET scanning before therapy. Patients with subsequently proven distant metastases were switched to alternative forms of chemotherapy, hormonal therapy, or both. RESULTS: Among the 48 patients evaluated with PET, 14 had abnormal FDG uptake, and metastases were suspected in 12. After simple clinical evaluation (plain x-ray, history), 10 sites that were suggestive of abnormality remained. Further work-up revealed that four sites were metastases. Proven false positivity occurred in one patient with sarcoidosis. In the other five patients, the reason for abnormal FDG uptake (liver, lung, bone) remained unclear, and patients were treated as planned. Eleven months later, distant metastases were found in one patient at sites unrelated to the previous FDG uptake. CONCLUSION: The addition of FDG PET to the standard work-up of patients with LABC may lead to the detection of unexpected distant metastases. This may contribute to a more realistic stratification between patients with true stage III breast cancer and those who are in fact suffering from stage IV disease. Abnormal PET findings should be confirmed to prevent patients from being denied appropriate treatment.

Adenocarcinoma↗
PubMed2004

Reduced growth, increased vascular area, and reduced response to cisplatin in CD13-overexpressing human ovarian cancer xenografts.

PURPOSE: Expression of aminopeptidase N/CD13 can be detected in several solid tumor types. Thus far, the role of CD13 in ovarian cancer has not been studied. We have investigated the expression pattern and biological function of CD13 in ovarian cancer. EXPERIMENTAL DESIGN: First, we studied the expression of CD13 in ovarian cancer tissue of 15 patients representing three different histological types (5 patients each) by immunohistochemistry. We then stably transfected the IGROV-1 human ovarian cancer cell line with a CD13 expression vector and examined the biological effect of CD13 in vitro and in vivo. RESULTS: The expression of CD13 in ovarian cancer was associated with the histological subtype: CD13 expression in tumor cells was observed in 80-100% of the patients with a serous or mucinous carcinoma and in only 20% of the clear cell carcinoma patients. In all patients' tumor samples, CD13-positive blood vessels were present. CD13 overexpression in IGROV-1 cells did not affect in vitro cell growth and sensitivity to doxorubicin, cisplatin, or gemcitabine. CD13 overexpression reduced invasion in Matrigel, which appeared to be independent of the aminopeptidase activity of CD13. Furthermore, the growth rate of IGROV-1/CD13 xenografts was reduced. The area of the vessel lumens was enlarged in a small percentage of vessels in the CD13-overexpressing xenografts. In addition, the CD13-overexpressing tumors were less sensitive to cisplatin. CONCLUSIONS: CD13 is expressed in tumor as well as endothelial cells in human ovarian cancer. Our results suggest that CD13 overexpression affects ovarian cancer growth, vascular architecture, and response to chemotherapy. Further elucidation of the mechanism of the observed effects of CD13 is warranted to better understand its role in the pathophysiology of ovarian cancer.

Adenocarcinoma, Clear Cell↗
PubMed2004

Conditionally replicative adenovirus with tropism expanded towards integrins inhibits osteosarcoma tumor growth in vitro and in vivo.

PURPOSE: The clinical course of osteosarcoma (OS) demands the development of new therapeutic options. Conditionally replicative adenoviruses (CRAds) represent promising agents for the treatment of solid tumors, because CRAds have an intrinsic replication capacity that allows in situ amplification and extensive tumor infection through lateral spread. The CRAd AdDelta24 has been developed to replicate selectively in cells with a defective retinoblastoma (Rb) pathway. Because genetic alterations in the Rb pathway are frequently observed in OS, AdDelta24 might be useful in the treatment of this cancer. EXPERIMENTAL DESIGN: Because the lack of Coxsackie adenovirus receptor on OS cells limits the efficacy of CRAd treatment, we explored alternative target molecules on OS. Insertion of an Arg-Gly-Asp (RGD-4C) integrin-targeting motif into the adenovirus fiber knob expanded tropism toward the alpha(nu)beta(3) and alpha(nu)beta(5) integrins. The oncolytic capacity of the CRAd Ad5-Delta24RGD was tested on primary OS cells in vitro and in vivo. RESULTS: The alpha(nu)beta(3)and alpha(nu)beta(5) integrins are abundantly expressed on OS cells. RGD-mediated infection augmented adenovirus infection of primary OS cells by two orders of magnitude. Ad5-Delta24RGD was shown to be highly active in killing human OS cell lines, as well as primary cell cultures. Furthermore, intratumoral injections with Ad5-Delta24RGD into established human OS xenografts that were derived directly from a patient with OS refractory for chemotherapeutic treatment caused a significant tumor-growth delay. Furthermore, adenoviral particles could be detected in tumor cells 25 days posttumor injection. CONCLUSIONS: Targeting adenovirus toward integrins rendered OS cells more sensitive to killing by Ad5-Delta24RGD. These findings suggest that Ad5-Delta24RGD has potential for use in OS treatment.

Adenoviridae↗
PubMed2004

The immunoregulatory role of CD1d-restricted natural killer T cells in disease.

Natural killer T (NKT) cells constitute a T cell subpopulation that shares several characteristics with NK cells. NKT cells are characterized by a narrow T cell antigen receptor (TCR) repertoire, recognize glycolipid antigen in the context of the monomorphic CD1d antigen-presenting molecule, and have the unique capacity to rapidly produce large amounts of both T helper (Th) 1 and Th2 cytokines. Important roles of NKT cells have now been demonstrated in the regulation of autoimmune, allergic, antimicrobial, and antitumor immune responses. Here, we review the immunoregulatory role of NKT cells in disease and discuss NKT cell based immunotherapeutic strategies.

Adjuvants, Immunologic↗
PubMed2004

Pronounced antitumor efficacy by extracellular activation of a doxorubicin-glucuronide prodrug after adenoviral vector-mediated expression of a human antibody-enzyme fusion protein.

Tumor-specific activation of the glucuronide prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate (DOX-GA3), by beta-glucuronidase present in necrotic tumor areas might be improved after transduction of tumor cells to secrete a targeted form of beta-glucuronidase. To that end, we constructed an adenovirus vector, designated Ad/C28-GUSh, encoding human beta-glucuronidase fused to a human single-chain Fv (scFv) against the epithelial cell adhesion molecule (EpCAM), C28, and preceded by a signal sequence for secretion. Antibody specificity and enzyme activity were retained in the fusion protein secreted by tumor cells infected with Ad/C28-GUSh. Diffusion of fusion protein from transduced tumor cells within MCF-7 multicellular spheroids was visualized by immunohistochemistry. Treatment of spheroids with Ad/C28-GUSh and DOX-GA3 resulted in growth inhibition comparable to treatment with doxorubicin alone. Treatment of well-established FMa human ovarian cancer xenografts with intravenous injection of DOX-GA3 (500 mg/kg) resulted in a tumor volume-doubling time of 23.8 days compared to 8.0 days for phosphate-buffered saline (PBS)-treated mice. Intratumoral administration of Ad/C28-GUSh before DOX-GA3 enhanced the growth inhibition and increased the tumor volume-doubling time to 43.1 days (p < 0.01), while virus alone had no effect. Thus, we have successfully shown that an adenovirus vector encoding a secreted, targeted form of human beta-glucuronidase can further improve DOX-GA3 monotherapy.

Adenoviridae↗
PubMed2003

Protein expression of B-cell lymphoma gene 6 (BCL-6) in invasive breast cancer is associated with cyclin D1 and hypoxia-inducible factor-1alpha (HIF-1alpha).

B-cell lymphoma gene (BCL-6) upregulation contributes to immortalization of mouse embryo fibroblast and primary B cells via upregulation of cyclin D1. As cyclin D1 overexpression is a common phenomenon in different cancers, BCL-6 protein overexpression may not be restricted to lymphomas. In this study, expression of BCL-6 was investigated by immunohistochemistry on paraffin-embedded specimens from 150 breast cancer patients and 10 specimens of normal breast tissue. The results showed BCL-6 overexpression (> or =10% of cells) in 24/150 (16%) breast cancer patients, whereas in normal breast low expression (<1%) of BCL-6 was observed. In linear regression analysis BCL-6 expression was associated with cyclin D1 (r=0.197, P=0.016). Further, in chi2 analyses, BCL-6-positivity was associated with overexpression of p53 (P=0.016), and hypoxia-inducible factor-1alpha (P<0.001). Involvement of BCL-6 in breast carcinogenesis is further underscored by comparative genomic hybridization analysis that showed gains at the BCL-6 locus (3q27) in 14/86 (16%) breast cancer tissues. The cases with amplification in BCL-6 showed an increased (25%) incidence of BCL-6 protein overexpression. Thus, this study is the first to show that BCL-6 oncogene activation plays a role in cancers other than lymphomas.

Breast Neoplasms↗
PubMed2003

Simulation model of doxorubicin activity in islets of human breast cancer cells.

During cytotoxic chemotherapy, cancer cells are exposed to a dynamic concentration-versus-time curve. Besides the area under this curve, the shape of this curve may determine the cytotoxic effect. This report describes the concept that cell damage is determined by the molar drug accumulation history inside the tumor cells. Cell numbers of large populations of human MCF-7 cells exposed to three different doxorubicin concentration-versus-time profiles were recorded for 31 days. The drug accumulation history in the cells was calculated using cellular drug transport parameters derived from doxorubicin uptake and efflux measurements on MCF-7 cells attached to culture dishes. Recovery of the proliferation rate of a cell population after drug exposure was described using a mathematical model of cell damage. The model fitted well to the proliferation assays. It allowed for comparison of the effects of changes in doxorubicin concentration-versus-time profiles in vitro. The model was then used to predict the effect of the changes in the doxorubicin concentration profile in vivo, in tumor islets, after a bolus injection of doxorubicin. In the model doxorubicin exposure resulted in less cell damage inside the tumor islets than at the rim.

Antineoplastic Agents↗