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Biomedical subjects

A Goldin

Publications and source records attributed to A Goldin.

At least 19 recordsLinked to original sources
PubMed1989

Inhibition of the covalent binding reaction of complement component C4 by penicillamine, an anti-rheumatic agent.

D(-)-Penicillamine [D(-)-beta beta-dimethylcysteine] is an anti-arthritic drug, but its use is limited by adverse side effects, which include problems in immune-complex clearance. Complement is important as a source of inflammatory mediators in rheumatoid arthritis and is also involved in immune-complex clearance. Thus inhibition of the complement cascade would be likely to contribute to both the therapeutic and the toxic effects of penicillamine. It is shown that penicillamine and cysteine are potent inhibitors of the covalent binding of activated complement component C4 to immune complexes. [35S]Cysteine itself becomes covalently bound to C4b through the thioester site. Penicillamine and cysteine are more reactive with the C4A isotype than with the C4B isotype of the HLA class III protein C4. The limited amino acid sequence differences between C4A and C4B include a cysteine/serine interchange, and it is suggested that the cysteine residue in C4A contributes to the increased rate of reaction of C4A with the alpha-amino-beta-thiol compounds.

Anaphylatoxins↗
PubMed1988

Therapeutic and pharmacological studies of tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue.

Tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue, showed greater therapeutic efficacy after i.p. administration than either cis-dichlorodiammineplatinum (II) (cisplatin) or cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (carboplatin) in mice bearing i.p. implanted L1210 leukemia. At an optimal dose of 5.7 mg/kg/injection given as a single dose on days 1, 5, and 9, tetraplatin increased the median life span over controls by more than 566% with 5 of 8 long-term (50-day) survivors. In contrast, cisplatin at the same optimal dose increased survival by 186% with 2 of 8 long-term survivors, and carboplatin at an optimal dose of 75.6 mg/kg/injection increased survival by only 120% with no long-term survivors. Tetraplatin also was more effective than cisplatin when treatment was delayed until days 3, 7, and 11 after i.p. implant. A combination of tetraplatin and Adriamycin in mice bearing i.p. implanted L1210 leukemia produced more long-term survivors over a wider range of doses than could be achieved with either drug alone. Tetraplatin at 5.7 mg/kg/injection and Adriamycin at 3 mg/kg/injection on days 1, 5, and 9 increased survival by more than 566% with 8 of 8 50-day survivors. Using the same treatment schedule, combinations of tetraplatin with either cisplatin, carboplatin, daunomycin, or 5-fluorouracil did not produce therapeutic efficacy greater than that seen with tetraplatin alone. The in vitro cellular uptake of platinum by L1210 cells at 37 degrees C was about 4-fold higher after exposure to tetraplatin compared to cisplatin following a 2-h incubation at the two concentrations examined (2.5 and 5 micrograms/ml). Comparative pharmacological studies were performed in rats at a single dose of 3 mg/kg i.v. The t1/2 beta for total platinum in plasma was 29.10 h (7.47 h for unbound platinum) after the administration of tetraplatin and 23.70 h (13.09 h for unbound platinum) after cisplatin. By 48 h the urinary excretion of platinum after tetraplatin and cisplatin was 30.1% and 41.4%, respectively. Tissue distribution of platinum was similar after either complex. Thus, tetraplatin has similar pharmacological properties to cisplatin and like cisplatin is a candidate for combination chemotherapy. However, tetraplatin may be superior to cisplatin in some therapeutic situations based on its greater efficacy against selected tumors.

Animals↗
PubMed1987

Metastatic potential of four human melanoma xenografts in young athymic mice following tail vein inoculation.

We have investigated the lung colonizing ability of four newly established human metastatic melanoma xenografts, designated CRML1, CRML2, CRML3, and CRML4 following i.v. tail vein inoculation into 3- to 4-week-old gnotobiotic CD-1 athymic mice. The experimental metastatic potential of the tumors was assessed from the primary tumor samples through eight progressively growing s.c. passages. CRML1 and 2 were investigated in detail; five sublines (two from CRML1 and three from CRML2) were established from these tumors with various growth rates and lung colonizing abilities. The histopathologies of the patients' biopsies and the s.c. passaged parental lines were compared with these i.v.-derived sublines as one measure of tumor heterogeneity, in conjunction with the kinetics of lung tumor formation. The frequency and distribution of extrapulmonary tumor growth was also investigated after i.v. inoculation. In general, it reflected the clinical distribution of metastases, although their frequency of appearance was reduced. While CRML3 was the most aggressive disease clinically, it did not demonstrate the reproducible experimental metastasis of the other lines. CRML4 produced lung colonies routinely, but with latency periods of 20 weeks or more. On the other hand, the most rapidly growing sublines of CRML1 and CRML2 essentially replaced the normal lung tissue within 4 to 6 weeks following inoculation of 10(5) cells. The two sublines of CRML1 with higher effective metastatic potential were maximally able to colonize the lungs within only two i.v. cycles in one case, while the other line required six i.v. to i.v. passages to reach its maximum ability. In CRML2, two sublines were identified that rapidly increased in their lung colonizing ability, while another line remained effectively equal to the parental s.c. line over four cycles of reinoculation i.v. These results demonstrated that the athymic mouse can serve as a model for experimental metastasis of human tumors, and that aspects of the metastatic heterogeneity of these tumors can be investigated by using this system.

Animals↗
PubMed1986

5-Fluorouracil treatment of a human colon adenocarcinoma implanted in the subrenal capsule site of athymic mice.

5-Fluorouracil was used in the treatment of a recently established. human adenocolon carcinoma implanted in the subrenal capsule site of athymic mice as part of a program to determine the relative effectiveness of antitumor agents in the treatment of human tumors grown as xenografts and in the clinic. 5-Fluorouracil treatments resulted in a dose-dependent inhibition of tumor growth under the two examined schedules (five daily doses and three doses every 4 days) when administered either i.v. or i.p. The various schedules and routes resulted in similar patterns of antitumor effects when the data were based on the endpoints of either final tumor weight, change in tumor weight, or relative tumor weight. Assessments of cell viability based on histological examination of tumored kidneys resulted in a downward displacement of the dose-response curves but did not alter their shape or the interpretation of the data. Although approximately 1-mm3 tumor fragments were implanted, variability of size was allowed. Tumor growth was not dependent on the initial size of the implant, as shown by a comparison between the initial individual or average tumor sizes and the final individual or average tumor sizes, respectively. The antitumor effects of the 5-fluorouracil could have been determined on the basis of final tumor weight alone. The inhibition of tumor growth was accompanied by weight loss in treated mice as compared with controls. At lower doses, however, the weight loss of the mice was not extensive, which indicated that the inhibition of tumor growth was, at least in part, attributable to some selective antitumor action of the 5-FUra. The greatest inhibition of tumor growth, however, was accompanied by the most extensive animal weight loss. This correlation raised the question of the degree to which the tumor growth inhibition observed was a consequence of nonspecific drug toxicity to the host. The current results stress the importance of detailed investigations into the nature of host-tumor parameters in order to assess the antitumor activity of candidate drugs in the treatment of human tumor xenografts.

Adenocarcinoma↗
PubMed1985

The effectiveness of the anthracycline analog 4'-epidoxorubicin in the treatment of experimental tumors: a review.

The current report presents the data of the Division of Cancer Treatment of the National Cancer Institute (NCI) on the antitumor activity of the anthracycline antibiotic 4'-epidoxorubicin in experimental tumor systems. Direct comparisons are made with doxorubicin in individual experiments, and the data are related to those of earlier studies in the form of a review of experimental activity, in order to assess the relative activity of 4'-epidoxorubicin and doxorubicin. The experimental test models utilized by the NCI for these studies included the leukemias P388 and L1210, B-16 melanoma, Lewis lung carcinoma, the colon tumors 26 and 38, and the mammary tumors CD8F1 and C3H16/C. The human tumors growing in xenograft in athymic mice included the models LX-1 lung tumor, CX-1 colon tumor, and MX-1 mammary tumor. Additional comparisons were made with the tumor models Gross leukemia, sarcoma 180, MSV-induced sarcoma, MS-2 tumor, and a variety of human tumors growing in athymic mice, as well as with in vivo toxicologic and in vitro cytotoxicity models. Although for 4'-epidoxorubicin there is only a minimal alteration of the configuration of the doxorubicin molecule, quantitative comparison of 4'-epidoxorubicin and doxorubicin revealed not only similarities but also differences in biological activity. Both drugs showed activity against a broad spectrum of experimental tumors, with 4'-epidoxorubicin more effective against some tumors and equally effective against others. 4'-Epidoxorubicin evidenced less toxicity than doxorubicin in both acute and chronic toxicity studies with retention of therapeutic effectiveness and showed reduced cardiotoxicity. With 4'-epidoxorubicin there resulted a higher therapeutic index and therapeutic ratio, permitting the use of higher dosage and a greater margin of safety. The preclinical differences in therapeutic and toxicologic manifestations of 4'-epidoxorubicin, reflecting apparent alterations in pharmacologic properties and mode of action in comparison with doxorubicin, support the broad spectrum clinical trials of this already-demonstrated clinically active drug.

Animals↗
PubMed1984

Dosing and sequencing for antineoplastic synergism in combination chemotherapy.

The success that has been achieved in combination drug chemotherapy of neoplasia is attributable to the attention that has been focused on factors pertaining to dosing and sequencing. These factors take into account both the tumor and the host on treatment with two or more drugs and are discussed under the following headings: (a) drug toxicity for the host; (b) drug ratios; (c) drug scheduling and sequencing; (d) body burden and scheduling; (e) host protection and scheduling; (f) synchronization and scheduling; and (g) prevention and treatment of tumor cell infiltration, sequestration, resistance, and metastasis. In relation to the factors that may influence therapeutic outcome, examples are provided for combination chemotherapy in which therapeutic synergism has been achieved in experimental tumor models. The importance of further studies on dosing and sequencing in order to maximize therapeutic response is discussed.

Animals↗
PubMed1984

Increased immunogenicity of murine lymphoma cells following exposure to gamma rays in vivo.

Studies performed in our laboratory showed that a marked increase in immunogenicity occurred in murine lymphoma cells exposed to a mutagenic compound such as 5 (3,3'-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC in vivo or in vitro. Subsequently, further experiments were conducted to test whether ionizing radiations would be able to affect the immunogenic properties of cancer cells in a mouse leukemia model. Male CD2F1 mice were inoculated with histocompatible L1210 Ha leukemia and treated with 400 R of total-body irradiation. A number of transplant generations were carried out with leukemic cells collected from irradiated donors, thus generating a "radiation treated line" (RTL). The immunogenicity of RTL cells increased significantly with respect to that of L1210 Ha line as early as 3 passages in vivo. However, no strong transplantation antigens comparable to those elicited by treatment with DTIC were found in RTL cells, even after a number of transplant generations. Combined effects of bis-chloroethyl-nitrosourea and weak anti-RTL responses of the host were markedly synergistic. Moreover, RTL lymphoma acquired strong immunogenic properties after a single cycle of DTIC treatment in vivo. These results may provide a model for exploiting radiation-induced increase of tumor cell immunogenicity for combined radio-immunochemotherapy.

Animals↗
PubMed1983

Relationships between plasma theophylline clearance, liver volume and body weight in children and adults.

The influence of liver volume and body weight on plasma theophylline clearance was investigated in asthmatic children and adults. A linear relationship (r = +0.99) was demonstrated between ideal body weight and liver volume estimated by an ultrasonic scanning technique. Age-related changes in liver volume-to-body weight ratio could account for only 30% of differences in plasma theophylline clearance (1/h/kg) between children and adults. It is summized that increased hepatic mixed function oxidase activity is the major contributor to the higher plasma theophylline clearance in children.

Adult↗
PubMed1983

Serotherapy of L1210 murine leukaemia--reasons for ineffectiveness of in vivo treatment by L.1 monoclonal antibody.

A monoclonal antibody (L.1), reacting in vitro specifically with L1210 leukaemia cells in a complement-dependent cytotoxicity assay (CDC), has been exploited for serotherapy studies. Different regiments of L.1 treatment of CD2F1 mice bearing the semi-syngeneic L1210 leukaemia did not prolong the life span of tumor-bearing animals. Moreover, the administration of L.1 did not enhance the antitumour effects of cyclophosphamide. Studies of in vivo localization showed that L.1 was able to bind specifically to L1210 leukaemic cells, although 30-40% of the cells remained negative. The presence of L.1 in mouse blood was demonstrated up to 15 days after the inoculation. On the other hand, in vivo administration of L.1 was probably accompanied by loss of the cytotoxic activity, perhaps through a mechanism of complement inactivation, since the presence of undiluted normal mouse serum in a CDC assay inhibited the cytotoxic activity of L.1. Moreover, serum from L.1-treated mice did not display any cytotoxic activity, although the presence of the antibody could be demonstrated by indirect immunofluorescence. Shedding of the antigen defined by L.1 was probably not responsible for the failure of the serotherapy, since the L.1 neutralizing antigen could be found in body fluids only long after the start of therapy.

Animals↗
PubMed1982

18F-5-Fluorouridine, a new probe for measuring the proliferation of tissue in vivo.

(1) Increased metabolic trapping of labeled fluorouridine reflects the interaction of three parameters in rapidly proliferating tissues: increased rates of intracellular phosphorylation, increased rates of transport, and increased rates of synthesis of RNA. (2) We have taken advantage of these metabolic phenomena, demonstrating in this paper that the uptake of 18F-5-fluorouridine, a positron-emitting radiopharmaceutical, can provide a very practical means for measuring changes in proliferative states of tissues in vivo. (3) Two major changes in proliferative states have been examined: one involves changes in growth of normal mouse tissues induced by pharmacological agents; the other involves tumor growth and neoplastic infiltration in mice and rabbits. (4) We describe tracer experiments with 18F-5-fluorouridylate, prepared by enzymatic means, and with 18F-5-fluorouridine, prepared by both enzymatic means and direct radiochemical procedures. (5) Uptakes of 18F after a pulse of 18F-5-fluorouridine were increased in mouse spleen following phenylhydrazine treatment to induce increased splenic erythropoiesis. (6) Uptakes of 18F in various mouse tissues were decreased following pretreatment with actinomycin D. This finding is consistent with the known inhibitory action of actinomycin on RNA synthesis. (7) Intracerebral Zimmerman ependymoblastoma tumors showed extraordinarily high uptakes of fluorine-18 in mice injected intravenously with 18F-5-fluorouridylate or with 18F-5-fluorouridine in contrast to very low uptakes by normal brain tissue. (8) After intracerebral injection of mice with suspensions of L1210 leukemia cells, distant organs such as lung, liver, and spleen became involved. These tissues showed significant increases of radioactivity after pulse labeling with 18F-5-fluorouridylate consistent with histological evidence for infiltration of these tissues by neoplastic cells. (9) Intramuscular VX2 carcinoma tumors in rabbits showed localized uptakes of 18F significantly higher than surrounding normal muscle tissue. (10) The most important clinical implication of the present work is the promise that 18F-5-fluorouridine uptakes can be followed in humans by positron emission tomography. This would provide a direct means of measuring different rates of in vivo proliferation in neoplasms, hematologic tissues and other organs undergoing rapid growth changes.

Animals↗
PubMed1981

Animal toxicology for early clinical trials with anticancer agents.

This analysis was carried out to assess quantitative and qualitative relationships between animal and human toxicology data with anticancer drugs. Among 21 chemotherapeutic agents, one-sixth LD10 in the mouse or one-third toxic dose low (TDL) in the dog corresponded to acceptable doses in man when experimental and clinical data were obtained at identical schedules and compared on a mg/m2 basis. The mouse and the dog largely differed in their tolerance to individual drugs. One-tenth LD10 in the mouse seemed always tolerated in the dog. On the average, these species were equally relevant for establishing the initial dose in man. A similar number of dose escalation steps would have been required in phase I clinical trials if the starting dose had been based on one-tenth LD10 in the mouse or the lowest value of one-sixth LD10 in the mouse and one-third TDL in the dog. These observations indicate that the starting dose in phase I clinical trials could be safely and efficiently based on one-tenth LD10 in the mouse. Prior verification that the resulting dose is not lethal or life-threatening in the dog could add further safety to this procedure. The predictive value (PV+) in man of organ system toxicity in animals depends upon the prevalence of this toxicity in man. In our study, PV+ was high (greater than 0.85) for common toxic effects in man, i.e., gastrointestinal intolerance and myelosuppression. PV+ declined dramatically (0.05 to 0.54) with rarer toxic manifestations. There was no clear superiority of animal findings over the mere knowledge of the prevalence of these findings in man. Thus, it would appear that routine and undiscerned investigation of organ system toxicity in animals is of questionable usefulness for the clinician experienced in early clinical trials with chemotherapeutic agents.

Animals↗