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Biomedical subjects

Philip Hahnfeldt

Publications and source records attributed to Philip Hahnfeldt.

11 recordsLinked to original sources
PubMed2006

Radiation-induced leukemia at doses relevant to radiation therapy: modeling mechanisms and estimating risks.

BACKGROUND: Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation-induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. METHODS: To extend the model to radiation-induced leukemias, we analyzed--in addition to cellular initiation, inactivation, and proliferation--a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors who were subjected to much lower radiation doses. RESULTS: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110,000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% CI = -0.2 to 1.9). CONCLUSIONS: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, with reasonable accuracy, risks for radiation-induced leukemia associated with exposure to therapeutic doses of radiation.

Adult↗
PubMed2005

Modeling intercellular interactions during carcinogenesis.

By modulating the microenvironment of malignant or premalignant cells, inhibitory or stimulatory signals from nearby cells can play a key role in carcinogenesis. However, current commonly used quantitative models for induction of cancers by ionizing radiation focus on single cells and their progeny. Intercellular interactions are neglected or assumed to be confined to unidirectional radiation bystander effect signals from cells of the same tissue type. We here formulate a parsimoniously parameterized two-stage logistic (TSL) carcinogenesis model that incorporates some effects of intercellular interactions during the growth of premalignant cells. We show that for baseline tumor rates, involving no radiation apart from background radiation, this TSL model gives acceptable fits to a number of data sets. Specifically, it gives the same baseline hazard function, using the same number of adjustable parameters, as does the commonly used two-stage clonal expansion (TSCE) model, so it is automatically applicable to the many data sets on baseline cancer that have been analyzed using the TSCE model. For perturbations of baseline rates due to radiation, the models differ. We argue from epidemiological and laboratory evidence, especially results for the atomic bomb survivors, that for radiation carcinogenesis the TSL model gives results at least as realistic as the TSCE or similar models, despite involving fewer adjustable parameters in many cases.

Carcinogenicity Tests↗
PubMed2004

Endostatin's antiangiogenic signaling network.

It is here demonstrated that the set of gene expressions underlying the angiogenic balance in tissues can be molecularly reset en masse by a single protein. Using genome-wide expression profiling, coupled with RT-PCR and phosphorylation analysis, we show that the endogenous angiogenesis inhibitor endostatin downregulates many signaling pathways in human microvascular endothelium associated with proangiogenic activity. Simultaneously, endostatin is found to upregulate many antiangiogenic genes. The result is a unique alignment between the direction of gene regulation and angiogenic status. Profiling further reveals the regulation of genes not heretofore associated with angiogenesis. Our analysis of coregulated genes shows complex interpathway communications in an intricate signaling network that both recapitulates and extends on current understanding of the angiogenic process. More generally, insights into the nature of genetic networking from the cell biologic and therapeutic perspectives are revealed.

Cells, Cultured↗
PubMed2003

Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects.

The multifaceted nature of the angiogenic process in malignant neoplasms suggests that protocols that combine antiangiogenic agents may be more effective than single-agent therapies. However it is unclear which combination of agents would be most efficacious and will have the highest degree of synergistic activity while maintaining low overall toxicity. Here we investigate the concept of combining a "direct" angiogenesis inhibitor (endostatin) with an "indirect" antiangiogenic compound [SU5416, a vascular endothelial growth factor receptor 2 (VEGFR2) receptor tyrosine kinase (RTK) inhibitor]. These angiogenic agents were more effective in combination than when used alone in vitro (endothelial cell proliferation, survival, migration/invasion, and tube formation tests) and in vivo. The combination of SU5416 and low-dose endostatin further reduced tumor growth versus monotherapy in human prostate (PC3), lung (A459), and glioma (U87) xenograft models, and reduced functional microvessel density, tumor microcirculation, and blood perfusion as detected by intravital microscopy and contrast-enhanced Doppler ultrasound. One plausible explanation for the efficacious combination could be that, whereas SU5416 specifically inhibits vascular endothelial growth factor signaling, low-dose endostatin is able to inhibit a broader spectrum of diverse angiogenic pathways directly in the endothelium. The direct antiangiogenic agent might be able to suppress alternative angiogenic pathways up-regulated by the tumor in response to the indirect, specific pathway inhibition. For future clinical evaluation of the concept, a variety of agents with similar mechanistic properties could be tested.

Adenocarcinoma↗
PubMed2003

SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro.

In recent decades, radiation research has concentrated primarily on the cancer cell compartment. Much less is known about the effect of ionizing radiation on the endothelial cell compartment and the complex interaction between tumor cells and their microenvironment. Here we report that ionizing radiation is a potent antiangiogenic agent that inhibits endothelial cell survival, proliferation, tube formation and invasion. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor were able to reduce the radiosensitivity of endothelial cells. Yet, it is also found that radiation induces angiogenic factor production by tumor cells that can be abrogated by the addition of antiangiogenic agents. Receptor tyrosine kinase inhibitors of Flk-1/KDR/VEGFR2, FGFR1 and PDGFR beta, SU5416, and SU6668 enhanced the antiangiogenic effects of direct radiation of the endothelial cells. In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668. Furthermore, ionizing radiation up-regulated VEGF and basic fibroblast growth factor in PC3 cells and VEGFR2 in endothelial cells. Together these findings suggest a radiation-inducible protective role for tumor cells in the support of their associated vasculature that may be down-regulated by coadministration of angiogenesis inhibitors. These results rationalize concurrent administration of angiogenesis inhibitors and radiotherapy in cancer treatment.

Angiogenesis Inhibitors↗
PubMed2003

Minimizing long-term tumor burden: the logic for metronomic chemotherapeutic dosing and its antiangiogenic basis.

The general utility of the maximum tolerated dose (MTD) paradigm, a strategy aimed at optimizing the chance of total tumor cell eradication, is here questioned. Evidence to date suggests that for many tumors the potential for eradication is in fact remote, with patients consistently demonstrating tumor cell presence subsequent to MTD treatments having eradicative intent. The failure to eradicate is attributed largely to the heterogeneous nature of the tumor. Heterogeneous cell populations demonstrate short-term refractoriness to up-front dose delivery, but "resensitize" as part of dose recovery, showing increased overall susceptibility to a given series of doses when delivered more evenly spaced. It is demonstrated: (1) that the minimization of total tumor burden, rather than complete eradication, may often be the more practical objective; and (2) that regularly spaced, "metronomic" dosing is the best way to achieve it. As a corollary, it is found that the more efficient ability of the tumor endothelial cells to resensitize following dosing predicts a targeting bias towards the endothelial compartment of a tumor when metronomic dosing is employed. This lends theoretical support to recent empirical studies showing that regularly spaced dosing schedules with no extended rest periods act more antiangiogenically, thereby delaying or avoiding the onset of acquired resistance.

Angiogenesis Inhibitors↗
PubMed2002

Chromosomes are predominantly located randomly with respect to each other in interphase human cells.

To test quantitatively whether there are systematic chromosome-chromosome associations within human interphase nuclei, interchanges between all possible heterologous pairs of chromosomes were measured with 24-color whole-chromosome painting (multiplex FISH), after damage to interphase lymphocytes by sparsely ionizing radiation in vitro. An excess of interchanges for a specific chromosome pair would indicate spatial proximity between the chromosomes comprising that pair. The experimental design was such that quite small deviations from randomness (extra pairwise interchanges within a group of chromosomes) would be detectable. The only statistically significant chromosome cluster was a group of five chromosomes previously observed to be preferentially located near the center of the nucleus. However, quantitatively, the overall deviation from randomness within the whole genome was small. Thus, whereas some chromosome-chromosome associations are clearly present, at the whole-chromosomal level, the predominant overall pattern appears to be spatially random.

Chromosome Painting↗
PubMed2002

PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis.

Several drugs approved for a variety of indications have been shown to exhibit antiangiogenic effects. Our study focuses on the PPARgamma ligand rosiglitazone, a compound widely used in the treatment of type 2 diabetes. We demonstrate, for the first time to our knowledge, that PPARgamma is highly expressed in tumor endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, we show that rosiglitazone suppresses primary tumor growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumor cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In our in vivo studies, rosiglitazone suppresses angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumors. These results suggest that PPARgamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.

Angiogenesis Inhibitors↗
PubMed2002

Using graph theory to describe and model chromosome aberrations.

A comprehensive description of chromosome aberrations is introduced that is suitable for all cytogenetic protocols (e.g. solid staining, banding, FISH, mFISH, SKY, bar coding) and for mathematical analyses. "Aberration multigraphs" systematically characterize and interrelate three basic aberration elements: (1) the initial configuration of chromosome breaks; (2) the exchange process, whose cycle structure helps to describe aberration complexity; and (3) the final configuration of rearranged chromosomes, which determines the observed pattern but may contain cryptic misrejoinings in addition. New aberration classification methods and a far-reaching generalization of mPAINT descriptors, applicable to any protocol, emerge. The difficult problem of trying to infer actual exchange processes from cytogenetically observed final patterns is analyzed using computer algorithms, adaptations of known theorems on cubic graphs, and some new graph-theoretical constructs. Results include the following: (1) For a painting protocol, unambiguously inferring the occurrence of a high-order cycle requires a corresponding number of different colors; (2) cycle structure can be computed by a simple trick directly from mPAINT descriptors if the initial configuration has no more than one break per homologue pair; and (3) higher-order cycles are more frequent than the obligate cycle structure specifies. Aberration multigraphs are a powerful new way to describe, classify and quantitatively analyze radiation-induced chromosome aberrations. They pinpoint (but do not eliminate) the problem that, with present cytogenetic techniques, one observed pattern corresponds to many possible initial configurations and exchange processes.

Algorithms↗