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Biomedical subjects

R M Schultz

Publications and source records attributed to R M Schultz.

At least 271 records · Page 15Linked to original sources
PubMed1973

Depressed cell-mediated immunity in newborn rabbits bearing fibroma virus-induced tumors.

Tumors were induced in adult and newborn rabbits by inoculation of fibroma virus. Whereas tumors completely regressed in adult rabbits by 3 weeks after virus inoculation, newborn rabbits supported tumor growth for 3 to 4 weeks. In the latter case, some animals died at this time, others survived with a gradual regression of the tumors over an additional period of 5 to 6 weeks. Virus neutralization studies demonstrated antibodies to fibroma virus in the serum from both adult and newborn tumor-bearing rabbits. Newborn rabbits with progressively growing tumors failed to elicit a delayed cutaneous hypersensitivity reaction to fibroma antigens, whereas adult rabbits showed strong reactions as early as 7 days after tumor induction. Similarly, macrophage migration inhibition tests revealed that the lymphocytes from newborn rabbits with progressively growing tumors were only weakly reactive to fibroma antigens, as compared to lymphocytes from adult tumorbearing rabbits. In contrast, newborn rabbits that survived and regressed the tumors demonstrated strong cell-mediated immunity both by skin testing and migration inhibition. Virus growth studies in cell culture demonstrated that fibroma was unable to replicate in peritoneal macrophages from either newborn or adult rabbits. No differences were observed in growth of the virus in macrophages from tumor-bearing rabbits. The significance of these observations is discussed in respect of the possible role of cell-mediated immunity in fibroma tumor regression.

Animals↗
PubMed1972

Specific macrophage immunity to vaccinia virus: macrophage-virus interaction.

Macrophage immunity to vaccinia virus was examined by measuring replication of vaccinia virus in immune and nonimmune rabbit peritoneal macrophages. Vaccinia virus multiplied in macrophages from normal rabbits but failed to replicate in macrophages from immune rabbits. The specificity of vaccinia restriction was demonstrated by the ability of myxoma virus to replicate in nonimmune and vaccinia-immune macrophages. Vaccinia virus absorbed equally well to immune and nonimmune macrophages, but only a small fraction of immune cells supported synthesis of virus antigen. Virus eclipse and infective center neutralization studies suggested that much of the virus remained at the plasma membrane of immune macrophages, even after prolonged incubation in culture. These data support our previous suggestions that macrophages may contribute to specific immunity against vaccinia virus.

Adsorption↗
PubMed1972

Cytotoxic antibody response to tumors induced in adult and newborn rabbits by fibroma virus.

Cells cultured from tumors induced in rabbits by inoculation of fibroma virus possessed virus-specific cell surface and cytoplasmic antigens. Tumor cell cultures were capable of a limited number of cell divisions before degenerating. Employing the (51)Cr-release test and the microcytotoxicity test, it was demonstrated that sera from rabbits with regressed fibroma tumors contained antibodies cytotoxic for cells infected in culture with fibroma virus. These sera were only weakly cytotoxic for cultured fibroma tumor cells. In addition, newborn rabbits bearing progressively growing tumors had serum antibodies cytotoxic for cells infected with fibroma virus in culture but not for fibroma tumor cells. Immunofluorescence studies also showed that the reaction of immune serum with the surface antigens of fibroma tumor cells was markedly weaker than with the surface antigens of cells infected with virus in culture. Furthermore, membrane cytotoxicity and immunofluorescence reaction were significantly reduced when cells were tested after prolonged incubation or cell division, or both, following infection with fibroma virus. The failure of tumors to regress in newborn rabbits in spite of the presence of cytotoxic antibodies is discussed in respect to a possible reduction or alteration of virus-specific surface antigens on proliferating tumor cells.

Animals↗
PubMed1970

Active Site of alpha-Chymotrypsin Activation by Association-Desolvation.

High reactivity toward alpha-chymotrypsin is observed for derivatives of beta-arylpropionic acids of varied structure-L-alpha-acylamido compounds, D-cyclized compounds, and, now, L-glycolamide esters. Compensating enthalpy and entropy effects are observed which appear to be caused by changes in water of solvation. High reactivity with varied structure, and physical evidence, appear to rule out induced fit and distortion as important for this enzyme. The high reactivity results from precise fit of the hydrolyzing group at the critical serine-imidazole junction, resulting from binding of the aryl group and restriction of rotation. Part of the energy of binding is used to desolvate the reactant groups of substrate and enzyme, decreasing activation energies by several kilocalories and raising reactivity by 10(3) or more. Solvation by water stabilizes many compounds, allowing them to be present in solution in biological systems. Their reactions may occur as their reactivity is increased when they are desolvated and brought from solution into association with reactive groups in enzymes, membranes, and structured particles.

Journal Article↗
PubMedDate not supplied

Functional identity between murine gamma interferon and macrophage activating factor.

We have previously suggested that two lymphokine activities-macrophage activating factor (MAF) and gamma interferon (IFN-gamma)-are mediated by the same molecule. Striking similarities were noted in their cellular biosynthesis, rate of inactivation with acid treatment and heating, and elution profiles on Sephacryl S-200. In addition, highly specific polyclonal antibodies to murine IFN-gamma neutralized MAF and IFN-gamma to a similar degree. However, definitive studies require a pure product and we now report that murine IFN-gamma that had been cloned and expressed in a simian nonlymphoid cell line shows MAF activity. But it is not yet known whether IFN-gamma is responsible for all the MAF activity in media conditioned by T cells as the possibility for MAF heterogeneity remains.

Animals↗
PubMedDate not supplied

Binding of the epoxide cryptophycin analog, LY355703 to albumin and its effect on in vitro antiproliferative activity.

Cryptophycin, isolated from the cyanobacterium Nostoc, is a cytotoxic dioxadiazacyclohexadecenetetrone which causes rapid depletion of microtubules in intact cells. In the present report, the effect of protein binding of a new synthetic cryptophycin analog, LY355703 (cryptophycin 52), is discussed. In handling the compound, it was found to bind extensively to surfaces, and a high degree of plasma protein binding was also observed (about 99% in human plasma). Similarly, while LY355703 displays potent antiproliferative activity against several human tumor cell lines in vitro (IC50s ranging from 12 to 40 pM), the addition of human or bovine serum albumin (BSA) to CCRF-CEM cells adapted to serum-free (UltraCHO) medium markedly reduced its anti-proliferative activity. For example, the IC50s for LY355703 in BSA at 0, 4 and 40 mg/ml were 2, 19 and 34 pM, respectively. In comparison, the IC50 only increased 2-fold (4210-8530 pM) for taxol over the same BSA concentration range. When log phase CCRF-CEM cells were exposed to 1 microM [3H]LY355703, there was a rapid accumulation of drug, so that LY355703 reached steady state within 10 min. The rate of LY355703 uptake in log-phase CCRF-CEM human leukemia cells was a linear function of concentration over a wide range (0.25-50 microM), although the cytotoxicity IC50 was 19 pM. Drug accumulation was not inhibited by sodium azide. Although cryptophycin was observed to bind extensively to albumin, binding did not markedly modulate cryptophycin uptake by CCRF-CEM cells. Overall, these results demonstrate that attention must be given to the binding properties of LY355703 and similar cryptophycins while handling these compounds, and that binding to albumin (and probably other cellular components as well) is a significant factor for interpretation of results both in vitro and in vivo.

Animals↗
PubMedDate not supplied

Role of thymidylate synthase in the antitumor activity of the multitargeted antifolate, LY231514.

The cytotoxicity of LY231514 was only partially alleviated by thymidine addition (5 microM) in GC3 human colon carcinoma cells, and complete protection required the addition of both hypoxanthine (100 microM) and thymidine. In contrast, the cytotoxic activity of tomudex (raltitrexed, ZD1694) was completely reversed by thymidine alone. MCF-7 human breast and H630 human colon carcinoma cells selected for resistance to tomudex and 5-fluorouracil, respectively via thymidylate synthase (TS) amplification demonstrated only modest resistance to LY231514 compared to tomudex. LY231514-induced cytotoxicity in these resistant cell lines was completely prevented by the addition of hypoxanthine (100 microM), indicating inhibition of purine de novo biosynthesis as a secondary target for LY231514 action. Thymidine at physiologic levels in mouse plasma (approximately 1 microM) produced only a 2.6-fold shift in the IC50 for LY231514-mediated cytotoxicity in GC3/cl1 cells compared to a 128-fold shift for tomudex. LY231514 treatment (i.p., qd x 10) significantly delayed tumor growth in the GC3 carcinoma xenograft model. However, a thymidine kinase-deficient mutant of this same tumor line demonstrated heightened sensitivity to the in vivo antitumor activity of LY231514 with complete regression of established tumors and a large number of tumor-free survivors after one course of treatment. The data demonstrate that inhibition of thymidylate synthase is a prominent mechanism for antitumor activity by LY231514, but important secondary sites of action exist for this multitargeted molecule.

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