Biomedical subjects

D Rideout

Publications and source records attributed to D Rideout.

7 recordsLinked to original sources

PubMed1991

A self-assembling protein kinase C inhibitor.

Previous studies have described a dicationic anticarcinoma agent that can chemically assemble in situ from monocationic phosphonium salts. The chemical combination of these monocationic precursors in the micromolar concentration range, occurring after their uptake by cells, was probably responsible for their synergistic inhibition of cell growth and for their selective cytotoxicity to Ehrlich ascites murine carcinoma cells relative to untransformed epithelial cells. Here, we report that the dicationic product that forms in this assembly reaction is an in vitro inhibitor of protein kinase C (PKC) alpha and beta 1 isoforms, exhibiting IC50 values of 20.4 microM and 35 microM, respectively. The monocationic precursors proved to be much weaker inhibitors of PKC (IC50 values greater than 200 microM). When PKC is exposed to combinations of the two precursors, the enzymatic activity decreases steadily as a function of time. Using dose-response data and HPLC kinetic studies, we show that when the two precursor compounds are added as a combination to PKC under these conditions, the rate of formation of the inhibitory product follows the observed time course of decline in PKC activity under identical conditions. We discuss the possibility that antiproliferative effects against carcinoma cells of the preformed dication and of the combined monocationic precursors involve inhibition of PKC.

Animals↗

PubMed1991

Combined modality therapy of Hodgkin's disease: 10-year results of National Cancer Institute of Canada Clinical Trials Group multicenter clinical trial.

The purpose of this study was to compare four methods of treatment for stage III-IV Hodgkin's disease. Between January 1972 and September 1976, 266 patients with stage IIIB, IVA, and IVB Hodgkin's disease from 21 cancer treatment centers across Canada were registered as eligible; 40 were found to be ineligible. Of the 226 remaining patients, only seven were followed for less than 10 years. All patients received three courses of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy, which induced a complete response (CR) in 36%; an additional 42% obtained adequate disease control. Patients were randomly assigned to (1) treatment with radiation to the abdomen and mantle (group AX3, 62 patients) or (2) continue their treatment with an additional three courses of MOPP (group A, 105 patients). For the A group, a second randomization took place 3 months later (regardless of status at that time) to (1) no further treatment (AC6, 23 patients), (2) radiotherapy to the abdomen and mantle (AX6, 48 patients), or (3) maintenance chemotherapy at 3-month intervals for 1 year (AC10, 26 patients). The survival of AX3 patients was somewhat better than for the A group, but the difference was not significant (P = .0565). However, there was a significant interaction (P = .0029) between age and treatment, so that among patients less than 30 years of age, the survival of the A group was better, whereas for older patients, treatment with AX3 resulted in improved survival. Age itself remained a significant prognostic factor for survival after controlling for the amount of radiotherapy delivered to the abdomen and the dose intensity of vincristine for the first three courses of chemotherapy. The addition of radiation therapy to MOPP significantly reduced the frequency of nodal relapses. These results suggest that combined modality therapy may be beneficial for some patients with Hodgkin's disease and that age must be carefully considered in interpreting the results of clinical trials in Hodgkin's disease.

Adolescent↗

PubMed1990

Synergism through direct covalent bonding between agents: a strategy for rational design of chemotherapeutic combinations.

Self-assembling chemotherapeutic agents are mixtures of relatively nontoxic precursors that can combine chemically under physiological conditions to form products with greater cytotoxic and/or antimicrobial activity than either of the precursors. Combinations that form products more rapidly in or near the target (tumor, pathogen, virally infected cell) than in normal tissues will exhibit target-selective synergism, thus exhibiting an antitarget selectivity that is greater than the selectivities of the product (e.g., a hydrazone) and of either precursor (e.g., a hydrazine derivative or ketone) used singly. This paper describes the target-selective cytotoxic synergism of a cationic aldehyde (A) and a cationic acylhydrazine (B) containing a triarylalkylphosphonium moiety against Ehrlich ascites carcinoma cells (ELA) in culture, in addition to reviewing previous work on self-assembling cytotoxins. The synergism between A and B is carcinoma selective when the ELA cells (the target) are compared to CV-1, an untransformed African green monkey kidney epithelial line. Like tetraphenylphosphonium and rhodamine 123, which are selectively concentrated in ELA cells relative to CV-1, A, B and the hydrazone C resulting from their reaction are lipophilic delocalized cations that selectively inhibit ELA growth relative to CV-1 growth. The hydrazone C is more growth inhibitory than either A or B for both cell lines. A combination of A with an unreactive analogue of B and a combination of B with an unreactive analogue of A did not synergistically inhibit ELA proliferation. The degree of synergism is greater against the ELA cells than against the CV-1 cells. These data, together with hydrazone formation kinetics, suggest that A and B are both concentrated together selectively inside the ELA due to the transmembrane potentials, reacting inside the ELA cells at a higher velocity than inside the CV-1 cells to form the more growth-inhibitory hydrazone C.

Animals↗

PubMed1989

A study of post-orchiectomy surveillance in stage I testicular seminoma.

A study of post-orchiectomy surveillance without radiation therapy was done in patients with histologically pure seminoma apparently confined to the testicle. Criteria for study entry included a negative physical examination, chest x-ray, bipedal lymphogram, excretory urogram, abdomino-pelvic computerized tomography scan and serum alpha-fetoprotein. Followup consisted of frequent clinical examination, repeat lymphograms, abdominal computerized tomography scans, chest x-rays and serum markers. The purpose of this study was to determine the percentage of patients cured by orchiectomy alone, percentage who ultimately required therapy for occult metastases beyond the testicle, sites of relapse, factors predictive of relapse, and over-all cure rate and treatment morbidity. Of 81 patients followed for 3 to 43 months (median 19 months) only 3 had relapse at 3, 5 and 18 months after orchiectomy with nonbulky retroperitoneal disease: 1 patient had disease 17 months after salvage infradiaphragmatic radiation therapy, 1 had an increase in beta-human chorionic gonadotropin 11 months after radiation therapy, presumably due to occult nonseminoma, and he is receiving chemotherapy, and 1 has not yet completed treatment. Further followup is necessary to determine ultimate survival, since a risk for later relapse exists. However, to date it does not appear as if the outcome has been compromised when surveillance was applied in place of routine adjuvant radiotherapy.

Combined Modality Therapy↗

PubMed1988

Environment-selective synergism using self-assembling cytotoxic and antimicrobial agents.

Environment-selective synergistic toxicity using combinations of aldehydes and hydrazine derivatives was demonstrated in two different model systems in vitro. Combinations of 5-nitro-2-furaldehyde with semi-carbazide and of 2-hydrazinopyridine with pyridine-2-carboxaldehyde, which can react in situ to form antimicrobial hydrazones, demonstrated greater degrees of synergism against the intracellular pathogen, Salmonella typhimurium, at pH 5 relative to pH 7.4. Combinations are more selectively toxic at pH 5 (vs pH 7.4) than individual precursors and preformed hydrazone products because acid catalysis of hydrazone formation plays a role only for the combinations. A combination of decanal and N-amino, N'-octylguanidine (AOG) exhibited more pronounced synergistic cytolytic activity against erythrocytes in 0% serum than in 1% serum. Serum protein binding of decanal inhibited the formation of the more cytotoxic hydrazone, N-decylidenimino,N'-1-octylguanidine (DIOG), from the less cytotoxic AOG and decanal, and serum protein binding of DIOG prevented this cytotoxin from reaching the cell membrane. Because decanal binding cannot play a role in the cytotoxicity of preformed DIOG, it was less selective for cells in 0% serum than the combination of AOG and decanal. The pH 5 and 0% serum environments represent very simple models for macrophage phagolysosomal compartments and poorly vascularized solid tumor interiors respectively. If environment-selective synergism can be used as a basis for target-selective synergism in other in vitro model systems and in vivo, self-assembling combinations could provide a basis for rational introduction of target-selective synergism into chemotherapeutic drug design.

Aldehydes↗

PubMed1986

Self-assembling cytotoxins.

Decanal and N-amino-N'-1-octylguanidine (AOG), combined at 28 microM each, mediated erythrocyte lysis within 80 minutes under physiological conditions. By contrast, no lysis was observed after 20 hours with either decanal (56 microM) or AOG (100 microM) alone. The pronounced synergism observed for these chemicals and similar reactive pairs of chemicals is due to the self-assembly of more cytotoxic hydrazones in situ. Decanal and AOG also exhibit synergistic activity against cultured human cells (HeLa) and bacteria (Escherichia coli J96). This synergism may be useful in the design of cytotoxins that would self-assemble selectively from nontoxic precursors within tumors, while sparing normal tissue.

Aldehydes↗

PubMed1986

Class III alleles and high-risk MHC haplotypes in type I diabetes mellitus, Graves' disease and Hashimoto's thyroiditis.

By typing a large quantity of family-based material for HLA-B, HLA-DR, C4, C2 and factor B, we were able to derive four-gene complement haplotypes (C4A, C4B, C2, BF) and six-gene MHC haplotypes (HLA-B, complement, HLA-DR). Fourteen six-gene MHC haplotypes showed linkage disequilibrium but exact frequencies could not be determined because it was not always possible to assign null C4 alleles in families where null genes were not clearly seen to segregate. Comparison of unrelated type I diabetes, Graves' disease and Hashimoto's thyroiditis patients with healthy unrelated controls revealed the following MHC allele associations: C4B*3, HLA-DR3 and HLA-DR4 with type I diabetes; BF*F1 and HLA-DR3 with Graves' disease; HLA-DR4 with Hashimoto's thyroiditis. By typing families of type I diabetes and Graves' disease patients we were able to derive two high-risk DR3+ MHC haplotypes for both type I diabetes and Graves' disease. These are HLA-B8 C4A*Q0 C4B*1 BF*S HLA-DR3 and HLA-B18 C4A*3 C4B*Q0 BF*F1 HLA-DR3, and these haplotypes account for most of the associations between these diseases and HLA-DR3. The MHC haplotype HLA-B15 C4A*3 C4B*3 BF*S HLA-DR4 also carries high risk for type I diabetes in this group of patients. Our data suggest that other DR4+ haplotypes, probably containing C4A*3 C4B*1, carry increased risk for type I diabetes whereas haplotypes containing DR4 and C4 C4A*3 C4B*Q0 do not. Our phenotype data suggest that DR4 in Hashimoto's thyroiditis is frequently associated with HLA-B44, C4A*3, C4B*1 and BF*S.

Alleles↗