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Biomedical subjects

L Milas

Publications and source records attributed to L Milas.

At least 163 records · Page 9Linked to original sources
PubMed1984

Inhibition of radiation carcinogenesis in mice by S-2-(3-aminopropylamino)-ethylphosphorothioic acid.

We have demonstrated that S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) given to mice prior to ionizing radiation inhibits development of radiation-induced sarcomas. The right hind legs of C3Hf/Kam mice were exposed to single doses of gamma-rays ranging from 3400 to 5700 rads. Thirty min before irradiation, approximately one-half of the mice were given i.p. injections of WR-2721 (400 mg/kg). Mice were checked for development of radiation-induced tumors within the irradiated tissue of legs from 250 up to 786 days after irradiation. Tumors first appeared in both groups of mice at approximately 300 days after irradiation. Thereafter, the rate of tumor development was slower in mice that received both WR-2721 and leg irradiation. At the end of the observation period, the overall actuarial tumor incidence in these mice was 26%, compared to 87% in mice exposed to radiation only. Since WR-2721 has the ability to protect against radiation carcinogenesis, it may also afford protection against the carcinogenic effect of alkylating agents.

Amifostine↗
PubMed1984

Protection by S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation- and cyclophosphamide-induced attenuation in antitumor resistance.

Studies were performed to investigate whether S-2-(3-amino-propylamino)ethylphosphorothioic acid (WR-2721) can protect antitumor immune rejection responses against the damaging effects of whole-body irradiation ( WBI ) and cyclophosphamide (CY). Among these damaging effects were radiation-induced enhancement of s.c. tumor take and radiation- and CY-induced enhancement of lung colonization by tumor cells injected i.v. The ability of WR-2721 to protect against WBI -induced decreased radioresponse of solitary tumors was also investigated. All experiments were performed with an immunogenic fibrosarcoma syngeneic to C3Hf/ Kam mice. WR-2721 was given i.p. at a dose of 400 mg/kg 30 min before WBI with gamma-rays or CY injection. WBI with 650 rads reduced the number of tumor cells needed for tumor take in 50% of animals from 5.1 X 10(4) cells in normal mice to 2.0 X 10(2). WR-2721 given before WBI almost entirely abolished the effect of WBI : the number of tumor cells needed for tumor take in 50% of animals was 1.4 X 10(4). Treatment of mice with WBI or CY increased the number of tumor nodules in the lung generated by fibrosarcoma cells injected i.v. 5 days later, in a linear dose response. WR-2721 greatly reduced this metastasis enhancement effect of WBI and CY with protection factors of 2.5 for WBI and 1.8 for CY. Fibrosarcomas of 8 mm in diameter exhibited a decreased radiocurability when growing in WBI mice: the dose of irradiation yielding local tumor control in 50% of animals in these mice was 5950 compared to a dose of irradiation yielding local tumor control in 50% of animals of 4160 rads in normal mice. WR-2721 given before WBI inhibited this effect of WBI : the dose of irradiation yielding local tumor control in 50% of animals was 5210 rads. The proportion of macrophages in tumors growing in WBI mice was significantly reduced, but not when WR-2721 was first given. WR-2721 greatly reduced the damaging effects of WBI and CY on natural killer cell activity. Therefore, WR-2721 was capable of protecting the immune mechanisms involved in antitumor resistance against WBI and CY. This might be of therapeutic benefit when WR-2721 is combined with radio- or chemotherapy.

Amifostine↗
PubMed1984

Leech salivary gland extract from Haementeria officinalis, a potent inhibitor of cyclophosphamide- and radiation-induced artificial metastasis enhancement.

Studies were designed to determine whether salivary gland extract (SGE) from the leech Haementeria officinalis could inhibit enhancement of lung tumor colonization induced by pretreatment of mice with cyclophosphamide (CY) or local thoracic irradiation (LTI). Tumor nodules in the lung were generated by i.v. injections of T241 sarcoma and FSA fibrosarcoma cells into syngeneic C57BL/6 and C3Hf/Kam mice, respectively. CY (200 mg/kg) was given i.p. 1 or 4 days prior to i.v. injection of tumor cells. In other mice, a single dose of 1000 rads of LTI was given 1 day before tumor cells. Three i.v. or i.p. injections of SGE at doses of 600 to 800 micrograms of protein per injection given at 2-hr intervals between 2 hr before and 4 hr after CY, LTI, or tumor cell injection strongly inhibited and, in some cases, abolished the artificial metastasis enhancing effect of CY and LTI. SGE was similarly effective in inhibiting the enhancement of lung colonization when given before or after cytotoxic agents. Using [125I]iododeoxyuridine-labeled tumor cells, it was observed that SGE did not affect the initial lodgement of tumor cells in the lung, but it greatly facilitated their subsequent release from the lung. In normal mice, the SGE was active when given on the day or 1 day before but not when given 4 days before tumor cells. The antimetastatic effect of SGE was ascribed to its anti-platelet-aggregating, anticoagulant, and antiproteolytic enzyme activities.

Animals↗
PubMed1983

Response of fibrosarcoma cell subpopulations to small doses of radiation delivered in situ.

The survival of cells from 2 tumor subpopulations after gamma-ray doses ranging from 1 to 19 Gy was determined using a lung colony assay. Methylcholanthrene-induced fibrosarcomas grown in the hind legs of C3H/Kam pathogen-free mice were irradiated in situ when the tumors were 8-10 mm in diameter. Single cell suspensions prepared from excised tumors were separated on a linear density gradient, and the clonogenicity of predominantly oxic Band 2 (density 1.08 g/cm3) and predominantly hypoxic Band 4 (density 1.14 gm/cm3) cells was measured. The surviving fraction of cells after doses of 1, 2, and 3 Gy was estimated from that measured after total doses of 5 Gy = 5 X 1 Gy, 10 Gy = 5 X 2 Gy, and 15 Gy = 5 X 3 Gy, under the assumption of equal effect per fraction (checked by estimating survival at 3 Gy after different numbers of fractions). Very little curvature was evident in the survival curves of Band 2 and Band 4 cells (beta/alpha = .013-.034 Gy-1). The initial segment of the survival curve of the predominantly oxic Band 2 cells was steeper (1Do = 3.6 Gy) than that of the predominantly hypoxic Band 4 cells (1Do = 5.2 Gy); both remained linear over a large range, to doses in excess of 3 Gy. These results imply that these tumor subpopulations will be insensitive, in their response to multifractionated regimens, to changes in size of dose per fraction in the range 0 to 3 Gy, a trait shared by two acutely responding normal tissues (murine testis and jejunum).

Animals↗
PubMed1983

Effect of tumor size on S-2-(3-aminopropylamino)ethylphosphorothioic acid and misonidazole alteration of tumor response to cyclophosphamide.

The influence of tumor size on the ability of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) or misonidazole (MISO) to alter cyclophosphamide (CY) antitumor activity was investigated, using a chemically induced fibrosarcoma (FSA) and a spontaneous fibrosarcoma (NFSA) in C3Hf/Kam mice. Tumors were of two sizes at the time of treatment, 8-mm leg tumors and 4-day-old micrometastases in the lung. The antitumor activity of CY and its modification were assessed by growth delay of leg tumors and the reduction in the number of lung metastases. Both measures of tumor response were more pronounced as the dose of CY increased, and FSA was more sensitive to CY than was NFSA. WR-2721 (400 mg/kg), given 30 min before treatment with CY, reduced the effectiveness of CY on both FSA and NFSA. This reduction in effectiveness of CY was only minimal for leg tumors (dose-modifying factors were 1.1 for FSA and 1.03 for NFSA) but remarkable for lung micrometastases (dose-modifying factors were 1.81 for FSA and 1.55 for NFSA). Protection increased with the increase in the dose of WR-2721 and was also dependent on the time of injection relative to CY. The greatest protection occurred when WR-2721 was given within 30 min before to 15 min after CY. Tumor size had the opposite effect on MISO from that on WR-2721. MISO (1 mg/g) enhanced the effect of CY more effectively for leg tumors than for lung micrometastases: dose-modifying factors were 1.74 for FSA and 2.21 for NFSA growing in the leg and 1.27 for FSA and 1.11 for NFSA lung micrometastases. Therefore, tumor size appears to be a very important factor in determining the extent of WR-2721- and MISO-induced modification of CY antitumor effect.

Amifostine↗
PubMed1983

Protection by S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation-induced leg contractures in mice.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was shown to provide marked protection against development of radiation-induced leg contractures in C3Hf/Kam mice whose legs were exposed to single doses of gamma-radiation. The radiation doses ranged from 3300 to 6200 rads delivered to the right hind thighs from two parallelly opposed 137Cs sources. WR-2721 was given i.p. 30 min before irradiation. The severity of radiation-induced leg contractures in untreated and WR-2721-treated mice was followed for 342 days after irradiation. The degree of leg contractures in both control and WR-2721-treated mice increased up to 100 days after radiation, when the change stabilized, remaining more or less at the same level to the end of the observation period. During this entire period, the severity of contractures was less in WR-2721-treated mice. The dose-modifying factor for the level of 5 mm reduction in leg extension was 1.5 at 182 days after irradiation. Since WR-2721 did not prevent the radiocurability of 8-mm fibrosarcomas growing in the same legs, these data imply that WR-2721 has a high potential for increasing therapeutic gain when combined with irradiation in the treatment of tumors of an appreciable size.

Animals↗
PubMed1982

Studies on the antitumor activities of pyrimidinone-interferon inducers. I. Effect against artificial and spontaneous lung metastases of murine tumors.

Since pyrimidinone compounds induce interferon production in several animal species and have potent antivirus activities, it appeared important to determine whether these compounds could also induce antitumor activities in their recipients. Pyrimidinone compounds 2-amino-5-bromo-6-methyl-4-pyrimidinone (ABMP), 2-amino-5-brome-6-phenyl-4-pyrimidinone (ABPP), and 2-amino-5-iodo-6-phenyl-4-pyrimidinone (AIPP) were studied for their activities against artificial lung metastases of the weakly immunogenic spontaneous fibrosarcoma NFSa, the moderately immunogenic spontaneous mammary carcinoma MCa-K, and the strongly immunogenic 3-methylcholanthrene-induced fibrosarcoma FSa syngeneic to inbred C3Hf/Kam mice. In addition, the therapeutic efficacy of ABPP and AIPP was also determined against spontaneous lung metastases of NFSa. ABPP and AIPP given ip at 250 mg/kg for 2 or 3 consecutive days before or after iv inoculatin of NFSa, FSa, or MCa-K cells greatly reduced the number of tumor nodules developed in the lungs. ABMP, however, was considerably less effective. ABPP and AIPP were also effective in therapy of spontaneous lung metastases of NFSa, especially when these compounds were given before surgical removal of the primary tumor. Neither ABPP nor AIPP was effective against tumor nodules growing in whole-body irradiated (WBI) mice, but both protected mice against enhancement of lung metastasis formation induced by exposure to whole-body irradiation. ABPP was more effective than AIPP in inducing production of interferon in normal mice. When treated with ABPP, WBI mice, however, were unable to produce interferon. These results show that 6-phenyl-pyrimidinone compounds induce strong antitumor activities in mice, which correlated with neither tumor immunogenicity nor the ability of these agents to induce interferon, but which depended on the immune status of the tumor host.

Animals↗
PubMed1982

Protective effects of S-2-(3-aminopropylamino)ethylphosphorothioic acid against radiation damage of normal tissues and a fibrosarcoma in mice.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) was investigated for its protective effect against radiation-produced damage of jejunum, testis, lung, hair follicles, and a fibrosarcoma of C3Hf/Kam mice. Most of these tissues were radioprotected, and the degree of radioprotection depended on the dose of WR-2721 and the time interval between administration of WR-2721 and radiation treatment. WR-2721 increased resistance of jejunal epithelial cells and spermatogenic cells to single doses of gamma-rays by factors of 1.64 and 1.54, respectively. Protection against hair loss was less pronounced; the dose-modifying factor here was 1.24. The radiation-induced acute damage of the lung expressed by the increased formation of tumor nodules in the lung was not decreased by treatment of animals with WR-2721 before radiation. In contrast, WR-2721 augmented the radiation-induced enhancement of metastasis formation in the lung. WR-2721 protected fibrosarcoma micrometastases in the lung against therapeutic effect of radiation by a factor of 1.238. In contrast, this compound had no effect on the therapy of an 8-mm fibrosarcoma growing in the legs of mice.

Amifostine↗
PubMed1981

Influence of splenectomy upon immunologic reactivity of patients with Hodgkin's disease.

Since most patients with Hodgkin's disease benefit from splenectomy, a study was designed to explore whether these beneficial effects could be attributed to the recovery of patients' immunologic reactivity. Using a series of ordinary skin test (PPD-tuberculine, Varidase and Candidin) determination of absolute T and B lymphocyte counts in peripheral blood and their mitogenic responsiveness, assessment of immunologic reactivity was performed in 28 Hodgkin's disease patients, prior to and 14 days after splenectomy. The results showed that overall immunologic reactivity of these patients was suppressed as judged by low absolute lymphocyte counts (1747.2 +/- 171.9), lower counts of T (592.0 +/- 92.1) and B cells (295.9 +/- 40.5) and their poor capacity to respond to phytohemagglutinin (PHA) (20342.6 +/- 3662.8 cpm), although the reactivity towards skin test antigens seemed to be well preserved. After splenectomy the reactivity improved, absolute lymphocyte counts raised to 2654.9 +/- 468.8 and were parallelled by an increase in T (936.7 +/- 138.0) and B cell counts (402.2 +/- 81.2). PHA reactivity recovered as well (26965.5 +/- 4035.6 cpm), however, its remained lower than in control cultures. Furthermore, the immunocompetence of patients' spleens was assessed. The possible influence of some suppressive mechanisms such as serum-blocking factor and prostaglandins is discussed.

Adolescent↗
PubMed1981

Therapy of artificial and spontaneous metastases of murine tumors with maleic anhydride-divinyl ether-2.

A 15,500 molecular-weight fraction of a pyran copolymer, (MVE-2) was investigated for its therapeutic efficacy against artificial lung metastases of a weakly immunogenic spontaneous fibrosarcoma (NFSa), a relatively strongly immunogenic fibrosarcoma (FSa), a moderately immunogenic spontaneous mammary carcinoma (MCa-K-, and a weakly immunogenic spontaneous mammary carcinoma (MDAH-MCa-4) syngeneic to C3Hf/Kam mice. In addition, the therapeutic efficacy of this polyanionic compound against spontaneous lung metastases of NFSa was also determined. Systemic i.v. or i.p. application of MVE-2 in doses ranging from 10 to 50 mg/kg body weight greatly reduced the number of artificial NFSa lung metastases and prolonged the survival of the mice. Multiple injections of MVE-2 given at weekly intervals were more effective than were single treatments. Although various treatment schedules with MVE-2 were capable of reducing the number of metastases and prolonging survival of tumor-bearing mice, no cures were observed. A therapeutic effect was also evident against spontaneous lung metastases of NFSa. The effect, however, was more profound when MVE-2 was given before rather than after surgical removal of the primary tumor. MVE-2 was not effective in mice exposed previously to whole-body or local thoracic irradiation. In contrast, MVE-2 protected mice against enhancement of lung metastases induced by exposure of the mice to these irradiations. NFSa growing i.m. promoted the formation of lung metastases from tumor cells given i.v. This concomitant enhancement of metastases was abolished by treatment of the mice with MVE-2. MVE-2 was also effective against tumor deposits in the other three tumors. The extent of its therapeutic efficacy was independent of tumor immunogenicity. These results suggest several approaches to the clinical application of MVE-2 and provide additional data on the therapeutic activity of the pyran copolymer derivatives in different animal models.

Animals↗