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C C Benz

Publications and source records attributed to C C Benz.

69 records · Page 4Linked to original sources
PubMed1990

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer.

A multicenter phase I pharmacokinetic study of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites. N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1-2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.

Administration, Oral↗
PubMed1990

Magnetic resonance imaging of implanted melanomas before and after chemotherapy. Relation to 31P magnetic resonance spectroscopy and tumor histology.

The early effects of in vivo platinum-rhodamine (PtR) chemotherapy on tumor high-energy phosphorous metabolism was investigated using phosphorus-31 (31P) magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and histologic examination in a subcutaneously implanted hamster melanoma model. PtR was chosen because of its potential antimitochondrial and antineoplastic properties. All melanomas were clearly observed on both T1- and T2-weighted images (T1WI and T2WI), with viable tumor regions generally characterized by low to intermediate intensity on T1WI and high intensity on T2WI. Necrotic regions were more variable in appearance, depending on the amount of cystic fluid and hemorrhage. No changes were detected on either T1WI or T2WI within 90 minutes of a tumoristatic dose of PtR (40 mg/kg) by visual examination, but slight differences were seen on calculations of relative signal intensities. However, this same dose of PtR caused a 50% drop in tumor ATP and phosphocreatine content (relative to Pi) measured by 31P MRS within 90 minutes of drug injection. Magnetic resonance spectroscopy appears to offer a sensitive means of detecting the earliest biochemical effects of chemotherapeutic agents that are known to affect tumor bioenergetics.

Animals↗
PubMed1990

Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers.

Racemic gossypol has been shown to have antitumor properties that may be due to its ability to uncouple tumor mitochondria or to its inhibitory effects on a variety of nonmitochondrial enzymes. We have studied the antimitochondrial and enzyme-inhibiting properties of gossypol in human carcinoma cell lines of breast (MCF-7, T47-D), ovarian (OVCAR-3) colon (HCT-8), and pancreatic (MiaPaCa) origin by comparing the effects of its purified (+)- and (-)-enantiomers. (-)-Gossypol shows up to 10-fold greater antiproliferative activity than (+)-gossypol in the cancer cell lines and in normal hematopoietic stem cells grown in vitro, with IC50 values ranging from 1.5 to 4.0 microM for the cancer cells and from 10 to 20 microM for the human marrow stem cells. As well, multidrug-resistant MCF/Adr cells appear more resistant to (-)-gossypol than their parental cell line. Electron microscopy indicates that the earliest ultrastructural change in tumor cells exposed to a cytotoxic (10 microM) concentration of (-)-gossypol is the selective destruction of their mitochondria. Consistent with this observation, 31P magnetic resonance spectroscopy detects pronounced changes in tumor cell high energy phosphate metabolism within 24 hr of (-)-gossypol treatment, manifest by 1.6- to greater than 50-fold differential reductions in the intracellular ratios of ATP/Pi, relative to (+)-gossypol-treated cell lines; the magnitude of these antimitochondrial effects correlates with the antiproliferative activity of (-)-gossypol. Northern blot RNA analyses suggest that treatment with a 5-10 microM dose of (-)-gossypol induces a transient increase in the expression of heat shock gene products, particularly hsp-70 transcripts. The mean 5-fold increase in (-)-gossypol-induced hsp-70 mRNA appears coincident with a comparable heat-stimulated increase in transcript levels, as compared with control or (+)-gossypol-treated cells. The enzyme-inhibiting properties of gossypol enantiomers were compared in cell-free assays measuring glutathione-S-transferase-alpha, -mu, and pi activities, calmodulin stimulation of cyclic nucleotide phosphodiesterase, and protein kinase C activity. Both enantiomers are near equivalent antagonists of calmodulin stimulation and protein kinase C activity, exceeding the potency of known inhibitors such as phenothiazines by as much as 50-fold. In contrast, (-)-gossypol is a 3-fold more potent inhibitor of glutathione-S-transferase-alpha and -pi isozyme activity, resulting in IC50 values of 1.6 and 7.0 microM, respectively, for these two isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1989

Expression of c-myc, c-Ha-ras1, and c-erbB-2 proto-oncogenes in normal and malignant human breast epithelial cells.

Short-term cultures of normal human mammary epithelial cells were used to determine the extent to which c-myc, c-Ha-ras1, and c-erbB-2 proto-oncogenes were expressed in proliferating normal cells. This level of expression was compared with that of primary tumor cells, malignant effusion cells, or permanently established breast cancer cell lines. Pure preparations of epithelial organoids from seven different reduction mammoplasty tissue samples yielded proliferating normal epithelial cells upon short-term tissue culture. In every sample, proto-oncogene transcript levels increased upon short-term culture of the epithelial cells. These levels often exceeded by 10-fold the levels measured in uncultured organoids from the same tissue. In four of the seven cultured normal breast samples, at least one of the proto-oncogenes increased its expression to a level equaling or exceeding that found in a proliferating breast cancer cell line, MCF7. One effusion metastasis sample and two primary ductal adenocarcinomas were also examined for proto-oncogene expression. The effusion metastasis sample expressed high levels of c-erbB-2 messenger RNA, in accord with its amplified gene copy number; otherwise, the levels of proto-oncogene transcripts were low in unprocessed tumor and uncultured organoids, but they increased with proliferation of the tumor cells in culture. These results indicate that the variable expression of these proto-oncogenes observed in breast biopsy specimens needs to be controlled for cellular growth rate or proliferation index. Furthermore, these findings suggest that dysregulated proto-oncogene expression, rather than overexpression per se, needs to be evaluated as a possible mechanism contributing to the development of human breast cancer.

Blotting, Northern↗
PubMed1989

The effect of gossypol and 6-aminonicotinamide on tumor cell metabolism: a 31P-magnetic resonance spectroscopic study.

31P-Magnetic resonance spectroscopy has been used to assess the changes in the levels of water-soluble phosphate pools in T47-D breast carcinoma cells induced by the antimitochondrial drugs, gossypol and 6-aminonicotinamide. A decrease in the NTP/Pi ratio occurred after treatment with gossypol. No change in the NTP/Pi ratio occurred on treatment with 6-aminonicotinamide; however, a substantial accumulation of 6-phosphogluconate was observed. Pretreatment of T47-D cells with gossypol prevented the accumulation of 6-phosphogluconate. This facile and non-invasive approach suggests that the oxidative part of the pentose-phosphate shuttle is an important source of reducing equivalents in T47-D cells. This pathway may prove to be a useful target for site-directed drug attack in carcinoma cell lines that require large quantities of NADP for the synthesis of fatty acids and steroids.

6-Aminonicotinamide↗
PubMed1989

Incidence of activating ras oncogene mutations associated with primary and metastatic human breast cancer.

To test the hypothesis that ras activation is involved in the final stages of breast cancer progression, we analyzed tumor DNA derived from 60 different patients and extracted from 40 invasive primary breast tumors, seven lymph node and skin metastases, nine metastatic effusions, and five established breast cancer cell lines. The polymerase chain reaction technique was used to amplify DNA fragments containing Kirsten-(Ki-), Harvey-(Ha-), and N-ras codons 12, 13, and 61 which were then probed on slot-blots with labeled synthetic oligomers to detect nonconservative single base mutations. Activating mutations were found in one of 40 primary tumors (Ki-ras codon 13), zero of seven lymph node and skin metastases, one of nine metastatic effusions (Ki-ras codon 12), and two of five cell lines (Ki-ras codons 12 and 13). These results indicate that activating ras mutations are rarely involved in either the initiation or metastatic progression of human breast cancer.

Breast Neoplasms↗
PubMed1989

Toremifene: pharmacologic and pharmacokinetic basis of reversing multidrug resistance.

Triphenylethylene compounds, such as tamoxifen, have shown chemosensitizing activity independent of estrogen receptor status in doxorubicin-resistant cells. We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX. In addition, we examined the chemosensitizing activity of unbound plasma toremifene and its metabolites isolated from patients treated with toremifene doses of 20 to 400 mg/d. MCF-7/DOX cells were exposed to ultrafiltrate plasma specimens in the absence and presence of doxorubicin. These latter studies were single-blinded. Toremifene and its major metabolites were capable of sensitizing multidrug-resistant cells to doxorubicin. The degree of chemosensitizing activity in vitro correlated with the plasma concentrations of toremifene and its metabolites (P less than .05). Plasma samples isolated from patients receiving high-dose toremifene (400 mg/d) had the greatest chemosensitizing activity. We present evidence that toremifene and its metabolites can sensitize resistant MCF-7/DOX cells to doxorubicin, that this effect is concentration-dependent, and that sensitizing activity can be detected at clinically achieved concentrations.

Blood↗
PubMed1989

Effects of c-myc overexpression on the growth characteristics of MCF-7 human breast cancer cells.

Amplification and overexpression of the c-myc protooncogene have been observed in 22 to 32% of primary human breast cancers, yet the exact role of this gene in mammary tumor progression is unclear. We sought to elucidate this role by overexpressing cloned myc genes in the human breast carcinoma cell line MCF-7. We found that augmented myc RNA levels were associated with slower in vitro growth rates, but that estrogen receptor levels, the requirement for estrogen for in vivo growth in castrated athymic nude mice, and sensitivity to the antiestrogen, tamoxifen were not altered. Furthermore, chemosensitivity to the cytotoxic agent, Adriamycin, was not affected. Lastly, overexpression of a transfected myc gene did not suppress endogenous myc levels unlike the findings in lymphoma cells. Thus our data suggest that the effect of augmented myc expression in human breast cancer cells is complex and may not induce more malignant patterns of growth as has been suggested for other human cancers.

Animals↗
PubMed1989

Detection of amplified oncogenes by differential polymerase chain reaction.

Oncogene amplification has been found in a variety of human cancers and may have prognostic importance. Therefore, techniques which facilitate detection of gene amplification could have wide applicability. We have devised a sensitive, rapid, and non-radioactive procedure for detecting alterations in gene copy number based on the polymerase chain reaction (PCR). In this technique, called differential PCR, a target gene and a single-copy reference gene are co-amplified by PCR in the same reaction vessel. The level of target gene amplification is reflected in the ratio between the two resulting PCR-product bands. We show that this method can detect as low as two-fold amplification of specific target genes. Furthermore, amplification of neu and the epidermal growth factor receptor gene could be detected in as few as 100 breast carcinoma cells or in single sections of formalin-fixed, embedded material.

Breast Neoplasms↗
PubMed1988

Use of the polymerase chain reaction technique to create base-specific ras oncogene mutations.

A modification of the polymerase chain reaction technique (PCR) technique, a primer-mediated enzymatic amplification of specific target sequences in genomic DNA, was used to introduce point mutations into copies of human ras oncogene sequences, and to amplify these mutated copies approximately 10(6)-fold. Of the two flanking oligomers used to amplify the DNA, one contained a single base mismatch with the targeted gene segment, either codon 12 or 61 from the Kirsten ras oncogene. Double-stranded fragments harboring any point mutation can be generated using the appropriate oligomer and constitute greater than 99.999% of the PCR-amplified fragments. The amplified DNA fragments are readily slot-blotted to nylon membranes to serve as positive hybridization controls in the search for gene mutations in human tissue specimens. The synthesis of single base mismatched DNA fragments was also used to demonstrate that oncogene mutations can be detected from mixed DNA populations as might be present in primary tumor specimens, even when the mutation of interest is present in only 5% of the amplified sample DNA.

Base Sequence↗
PubMed1988

Clinical pharmacokinetics of drugs used in the treatment of breast cancer.

This article reviews the absorption, bioavailability, distribution, metabolism, and elimination patterns of the agents most commonly used for the treatment of breast cancer. Although the majority of the pharmacokinetic studies reviewed have been examined in non-breast cancer patients, the kinetic findings are not significantly altered by disease state. The anthracyclines, antimetabolites, alkylating agents, antioestrogens and mitotic inhibitors are among the classes of agents used to treat breast cancer. Although extensively examined, cancer pharmacokinetic research has resulted in very few clinically relevant findings in breast cancer.

Antineoplastic Agents↗
PubMed1977

Acquired chronic candidiasis treated with transfer factor.

A patient with acquired chronic oral and vaginal candidiasis resistant to topical and parenteral therapy was found to have impaired cell mediated immunity to Candida antigen and loss of skin test response to tuberculin (Mantoux). Treatment with Candida-active transfer factor produced clinical remission lasting 1 year and restitution of in vitro and in vivo immune parameters. Relapse occurred while receiving a second lot of transfer factor from the same donor. Subsequent treatment with levamisole was associated with onset of agranulocytosis.

Adult↗
PubMedDate not supplied

Increased target specificity of anti-HER2 genospheres by modification of surface charge and degree of PEGylation.

Genospheres are cationic lipid-nucleic acid nanoparticles prepared by the assembly of the lipids and nucleic acids from an aqueous/organic liquid monophase that independently dissolves the components, where the resultant particles are homogeneously sized (70-110 nm), with efficiently incorporated and protected DNA. In the present study, we demonstrate pH-dependent modulation of the Genosphere surface charge using pH-titratable lipids. By incorporation of the lipids with titratable anionic or imidazole headgroups, Genospheres with neutral or anionic surface charge at neutral pH were produced and compared for cellular uptake and transfection of a reporter gene (luciferase) in culture of breast cancer cells. The extent of particle-cell association was also studied by fluorescent microscopy and quantified by cytofluorometery. The effects of Genosphere surface modification with poly(ethylene glycol) (molecular weight 2000) at low (0.5 mol %) and high (5 mol %) grafting densities, as well as the effects of HER2-receptor-directed targeting by an internalizable anti-HER2 scFv F5, linked via PEG spacer, were also studied. Inclusion in the Genosphere formulation of pH-titratable lipids CHEMS (cholesteryl hemisuccinate), CHIM (1-(3-(cholesteryloxycarbonylamino)propyl)imidazole), or DSGG (1,2-distearoyl-sn-glycero-3-hemiglutarate) rendered the particles surface-charge neutral or slightly anionic at neutral pH, and cationic at mildly acidic pH, as shown by zeta-potential measurements. In HER2-targeted systems, transfection activity and target specificity with HER2-overexpressing SKBR-3 breast cancer cells were dependent on Genosphere surface charge and PEGylation. The highest target specificity correlated with low cationic charge at neutral pH, while incorporation of 5 mol % PEG-lipid had only minor effects on Genosphere-cell association, internalization, and transfection activity. The implications of this work for potential in vivo applications are discussed.

Antibodies↗