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Biomedical subjects

Daniel D Von Hoff

Publications and source records attributed to Daniel D Von Hoff.

At least 19 recordsLinked to original sources
PubMed2006

Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells.

L-Asparaginase (l-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to l-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to l-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was >500-fold. Significantly, that potentiation was >700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and l-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use of l-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection.

Antineoplastic Agents↗
PubMed2006

Identification of an agent selectively targeting DPC4 (deleted in pancreatic cancer locus 4)-deficient pancreatic cancer cells.

One of the most common types of genetic alterations in cancer is the loss-of-function mutations in tumor-suppressor genes. Such mutations are usually very specific to cancer cells and present attractive and unique opportunities for therapeutic interventions. However, for various reasons, antitumor agents that target loss-of-function mutations have not been readily identified. In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations. We created DPC4 isogenic cell lines through the restoration of wild-type DPC4 in a pancreatic cancer cell line, BxPC-3, whose DPC4 gene was homozygously deleted. The isogenic cell lines were then used in the Pharmacological Synthetic Lethal Screening to evaluate compound libraries for antiproliferative activity and selectivity against DPC4 deficiency. After screening 19,590 compounds, we identified one lead compound, UA62001, which showed 4.6-fold selectivity against DPC4 deficiency in the DPC4 isogenic cell lines. UA62001 selectivity was also seen in another set of DPC4 isogenic cell lines generated by small interfering RNA knockdown. In addition, UA62001 was evaluated in commonly used pancreatic cancer cell lines. A fairly good correlation between DPC4 deficiency and UA62001 sensitivity was observed. Cell cycle analysis indicates that UA62001 arrests cells in S and G(2)-M phases. The results of microarray gene expression profiling and quantitative real-time reverse transcription-PCR suggest that cyclin B/CDC2 and minichromosome maintenance complexes might be the downstream cellular targets of UA62001.

Adenocarcinoma↗
PubMed2006

A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors.

PURPOSE: HMN-214 is an oral prodrug of HMN-176, a stilbene derivative that interferes with the subcellular spatial location of polo-like kinase-1, a serine/threonine kinase that regulates critical mitotic events. We conducted a dose escalation study of HMN-214 in patients with advanced cancer to assess the safety profile and pharmacokinetics of HMN-214 and to establish the maximum tolerated dose. EXPERIMENTAL DESIGN: Thirty-three patients were enrolled onto four dosing cohorts of HMN-214 from 3 to 9.9 mg/m2/d using a continuous 21-day dosing schedule every 28 days, with pharmacokinetic sampling during cycle 1. RESULTS: A severe myalgia/bone pain syndrome and hyperglycemia were dose-limiting toxicities at 9.9 mg/m2/d. A dose reduction and separate enrollment by pretreatment status (lightly versus heavily pretreated) was undertaken, with one dose-limiting toxicity (grade 3 bone pain) at 8 mg/m2/d. The maximum tolerated dose was defined as 8 mg/m2/d for both treatment cohorts. Dose-proportional increases were observed in AUC but not Cmax. There was no accumulation of HMN-176, the metabolite of HMN-214, with repeated dosing. Seven of 29 patients had stable disease as best tumor response, including 6-month stable disease in a heavily pretreated breast cancer patient. A transient decline in carcinoembryonic antigen in a patient with colorectal cancer was noted. CONCLUSIONS: The maximum tolerated dose and recommended phase II dose of HMN-214 when administered on this schedule was 8 mg/m2/d regardless of pretreatment status. Further development of HMN-214 will focus on patient populations for which high expression of polo-like kinase-1 is seen (i.e., prostate and pancreatic cancer patients).

Administration, Oral↗
PubMed2006

What's new in pancreatic cancer treatment pipeline?

There is still a substantial need for the development of new treatments for patients with pancreatic cancer. In this chapter, we will document that there is quite a bit of an increase in research activity with development in two major areas including (1) agents in the pipeline which already have hints of antitumor activity in patients with pancreatic cancer (therapeutic monoclonal antibodies and vaccines as well as more conventional cytotoxics), and; (2) agents in the pipeline which have just started (or will soon start) in clinical trial. These agents range from a gene-therapy approach to radiation enhancement to inhibitors of protein with increased expression in the very hypoxic pancreatic cancer tissue, to new monoclonal antibodies. With the level of investigational activity in pancreatic cancer it is very likely that several new therapeutic approaches to the disease will be forthcoming.

Adenoviridae↗
PubMed2006

Tubulin-associated drug targets: Aurora kinases, Polo-like kinases, and others.

Unrestrained cell division in cancer cells is dependent upon mitosis and its related processes. Therefore, a proven effective strategy in cancer treatment has been to interfere with the function of the mitotic spindle. Despite the success of these anti-mitotic agents, tubulin itself remains the only spindle-associated protein targeted by clinically approved agents. However, in recent years major advances have been achieved in targeting proteins that associate with tubulin and the mitotic spindle. Mitotic kinases such as the Aurora and Polo families are receiving significant attention due to their vital roles in assuring proper centrosome separation and chromosome segregation. Indeed, potent and selective inhibitors of these kinases have entered clinical trials. Similarly, the kinesins, particularly kinesin spindle protein (KSP), have emerged as potential therapeutic targets and inhibitors of KSP are currently under evaluation in the clinic. Although inhibitors have not been reported, mitotic checkpoint kinases (Mad2) and separase are additional potential targets for therapeutic intervention. Continued investigation of mechanisms regulating mitotic events will likely reveal additional proteins and pathways that could be potentially targeted and thereby provide more effective therapeutic options for cancer patients.

Antineoplastic Agents↗
PubMed2006

Drug targeting of the c-MYC promoter to repress gene expression via a G-quadruplex silencer element.

In this review, we describe the evidence for a parallel-stranded G-quadruplex in the purine-rich strand of the nuclease hypersensitivity element III(1) (NHE III(1)) of the promoter of c-MYC upstream of the P1 and P2 promoters. This biologically relevant G-quadruplex is a mixture of four loop isomers. The folding pattern of a nuclear magnetic resonance (NMR)-derived structure for the predominant loop isomer of this G-quadruplex has been obtained. This G-quadruplex has been demonstrated to be a silencer element, and the cationic porphyrin TMPyP4 has been shown to stabilize this G-quadruplex. Furthermore, TMPyP4 has been shown to repress c-MYC expression, and this effect is mediated through the silencer element. Last, the in vivo activity of TMPyP4 in xenograph models is presented.

Animals↗
PubMed2006

Targeting loss-of-function mutations in tumor-suppressor genes as a strategy for development of cancer therapeutic agents.

Two types of genetic mutations, gain-of-function in oncogenes and loss-of-function in tumor-suppressor genes, are important molecular bases of tumorigenesis of human cancers. Target-based drug discovery is the main stream of contemporary cancer therapeutic development but largely focuses on gain-of-function mutations in oncogenes. Loss-of-function mutations in tumor-suppressor genes are often neglected as therapeutic targets. In this review, we discuss the feasibility of targeting loss-of-function mutations in tumor-suppressor genes for the identification of cancer-specific therapeutic agents.

Antineoplastic Agents↗
PubMed2006

Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach.

Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1,3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G(2)-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development.

Antineoplastic Agents↗
PubMed2006

Comparing Aurora A and Aurora B as molecular targets for growth inhibition of pancreatic cancer cells.

To address the increased need to understand the similarities and differences in targeting Aurora A or Aurora B for the treatment of cancer, we systematically evaluated the relative importance of Aurora A and/or Aurora B as molecular targets using antisense oligonucleotides. It was found that perturbations in Aurora A and Aurora B signaling result in growth arrest and apoptosis preferentially in cancer cells. The biological fingerprints of Aurora A and Aurora B inhibition were compared and contrasted in efforts to identify the superior therapeutic target. Due to the different biological responses, we conclude that each Aurora kinase should be treated as autonomous drug targets, which can be targeted independently or in combination. We observed no advantages to targeting both kinases simultaneously and feel that an Aurora A-targeted therapy may have some beneficial consequences over an Aurora B-targeted therapy, such as mitotic arrest and the rapid induction of apoptosis.

Apoptosis↗
PubMed2005

Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies.

PURPOSE: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007. PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m(2) as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle). RESULTS: Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received > or = six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m(2), respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation. CONCLUSION: This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.

Adult↗
PubMed2005

PRL phosphatases as potential molecular targets in cancer.

The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL-1, PRL-2, and PRL-3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Individual PRLs are overexpressed in a variety of cancer cell lines and tissues when compared with their normal counterparts. More importantly, several recent studies have shown that PRL-3 is expressed at higher levels and at a greater frequency in colorectal cancer metastases compared with primary colorectal tumors and normal colon tissue. Ectopic expression of PRLs in nontumorigenic cells can influence proliferation and the migratory and invasive properties of cells, while knockdown of endogenous PRL-3 or PRL-1 in cancerous cells using small interfering RNA can abrogate cell motility and ability to metastasize in a mouse model. However, the exact biological function and cellular substrates of the PRLs remain unclear. This review will discuss what is known about the PRLs, what makes the PRLs possible attractive targets for therapeutic intervention, and the possible future directions in PRL biology and inhibitor identification.

Amino Acid Motifs↗
PubMed2004

Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.

By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines.

Antineoplastic Agents↗
PubMed2004

Hydrophilic camptothecin analogs that form extremely stable cleavable complexes with DNA and topoisomerase I.

Camptothecin (CPT) analogs that form more stable ternary complexes with DNA and topoisomerase I (termed cleavable complexes) show greater activity in their ability to inhibit tumor cell line growth in preclinical studies. Based on our earlier work, we hypothesized that analogs bearing hydrogen bonding moieties at the 7- through 10-position of CPT would result in more stable cleavable complexes. Consequently, we synthesized analogs with 7-mono-, 7-di-, and 7-trihydroxymethylaminomethyl groups. These analogs showed increasing cleavable complex stability as the number of hydroxyl groups was increased. The 7-trihydroxymethylaminomethyl analog of 10,11-methylenedioxycamptothecin (THMAM-MD) showed remarkable ternary complex stability with a half-life of 116 minutes. This is an order of magnitude more stable than any previously examined analog. Our in vitro analysis demonstrated that these analogs were all potent topoisomerase I poisons and could inhibit tumor cell growth in culture. We studied the effects of THMAM-MD in vivo in severe combined immunodeficient mice bearing HT-29 colon cancer and MiaPaCa-2 pancreatic cancer tumors. The THMAM-MD analog showed excellent, persisting activity in inhibiting tumor growth with both lines. Taken together, our results suggest that CPTs with hydrophilic, hydrogen-bonding groups at the 7-position hold the promise of excellent clinical activity.

Animals↗
PubMed2004

American Society of Clinical Oncology Technology Assessment: chemotherapy sensitivity and resistance assays.

PURPOSE: To develop a technology assessment of chemotherapy sensitivity and resistance assays in order to define the role of these tests in routine oncology practice. METHODS: The American Society of Clinical Oncology (ASCO) established a Working Group to develop the technology assessment. The Working Group collaborated with the Blue Cross and Blue Shield Association (BCBSA) Technology Evaluation Center. The Working Group developed independent criteria for selecting articles for inclusion in the ASCO assessment, and developed a structured data abstraction tool to facilitate review of selected manuscripts. One Working Group member and an ASCO staff member independently reviewed the 1,139 abstracts identified by the BCBSA comprehensive literature search, and by an updated literature search performed by ASCO using the BCBSA search strategy (1966 to January 2004). Of the 12 articles included in this technology assessment, eight were identified by the original BCBSA systematic review, one was provided by industry, and three were identified by the ASCO updated literature review. RESULTS: Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice. RECOMMENDATIONS: The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting. Oncologists should make chemotherapy treatment recommendations on the basis of published reports of clinical trials and a patient's health status and treatment preferences. Because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.

Antineoplastic Agents↗
PubMed2004

A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms.

PURPOSE: O(6)-alkylguanine-DNA alkyltransferase (AGAT) is modulated by methylating agents, which, in turn, abrogates nitrosourea resistance in preclinical studies. The feasibility of administering various sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TEM) in patients with advanced solid neoplasms was evaluated in this Phase I and pharmacological study to assess this premise in the clinical setting. The study also sought to determine the maximum tolerated dose (MTD) levels of BCNU and TEM as a function of Seq, to characterize the pharmacokinetic (PK) behavior of TEM administered both before and after BCNU, assess AGAT fluctuations in peripheral blood mononuclear cells (PBMCs), and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Sixty-three patients were randomized to receive treatment with oral TEM daily on days 1-5 and BCNU administered i.v., either on day 1 before TEM [Sequence (Seq) B-->T] or day 5 after TEM (Seq T-->B). Treatment was repeated every 6 weeks. Blood sampling for PK studies was performed on both days 1 and 5 of course one. PBMCs were sampled to evaluate major sequence-dependent effects on AGAT levels. RESULTS: Neutropenia and thrombocytopenia were the principal dose-limiting toxicities of the BCNU/TEM regimen. These effects were more prominent in patients receiving Seq T-->B, resulting in a much lower MTD of 80/100 mg/m(2)/day compared with 150/110 mg/m(2)/day for Seq B-->T. Notable antitumor activity was observed in patients with glioblastoma multiforme, sarcoma, and ovarian carcinoma. No sequence-dependent PK effects were noted to account for sequence-dependent toxicological effects. At the MTD level, AGAT activity in PBMCs decreased 3-fold, on average, and AGAT fluctuations did not appear to be sequence-dependent. CONCLUSIONS: The principal toxicities of the BCNU/TEM regimen were neutropenia and thrombocytopenia, which were consistent and predictable, albeit sequence-dependent. Seq T-->B was substantially more myelosuppressive, resulting in disparate MTDs and dose levels recommended for subsequent disease-directed evaluations (150/110 and 80/100 mg/m(2)/day for Seq B-->T and T-->B, respectively). Sequence-dependent differences in TEM PK do not account for this clinically relevant magnitude of sequence-dependent toxicity. The characteristics of the myelosuppressive effects of BCNU/TEM, the paucity of severe nonhematological toxicities, and antitumor activity at tolerable doses warrant disease-directed evaluations on this schedule.

Adult↗
PubMed2004

Topoisomerase I-DNA complex stability induced by camptothecins and its role in drug activity.

The mechanism of cytotoxicity of the camptothecin family of antitumor drugs is thought to be the consequence of a collision between moving replication forks and camptothecin-stabilized cleavable DNA-topoisomerase I complexes. One property of camptothecin analogs relevant to their potent antitumor activity is the slow reversal of the cleavable complexes formed with these drugs. The persistence of cleavable complexes with time may be an essential property for increasing the likelihood of a collision between the replication fork and a cleavable complex, giving rise to lethal DNA lesions. In this paper, we examined a number of camptothecin analogs forming cleavable complexes with distinctly different stabilities. Absolute reaction rate analysis was carried out for each derivative. Our results indicate that the stability of the cleavable complex is dominated by the activation entropy (DeltaS++) of the reversal process. We measured the relative lipophilicity of the CPT analogs by reverse-phase HPLC, but the DeltaS++ of complex reversal is not directly related to the lipophilicity of the CPT analog being used. We suggest that solvent ordering around the 7- through 10-position of the CPT ring may be responsible for reversal rate's dependence on DeltaS++. We demonstrate that the cleavable complex stability conferred by each camptothecin analog is directly correlated with the induction of apoptosis and cytotoxicity to tumor cells.

Animals↗