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Biomedical subjects

E E Miller

Publications and source records attributed to E E Miller.

At least 37 records · Page 2Linked to original sources
PubMed1984

Distribution and stability of [111In]bleomycin and its fractions in tumor-bearing mice.

The tissue distributions in glioma-bearing mice given injections of [111In]bleomycin (BLM) indicated that tumor concentrations and ratios of tumor to blood, muscle and brain for [111In]BLM-B2 and -A2 were higher than those for unfractionated [111In]BLM. Autoradiographs of electrophoretic gels of urine containing [111In]BLM or one of its fractions differed from those containing 111InCl3. [111In]BLM and its fractions (A2 and B2) were found to be stable in vivo. The fractions may be more useful in the clinic than [111In]BLM.

Animals↗
PubMed1984

Sequential changes in the activities of lipoprotein lipase and lipogenic enzymes during tumor growth in rats.

The sequential changes in lipid metabolism during tumor growth were evaluated in inbred Lewis rats bearing a mammary adenocarcinoma (AC33). Serum lipids, insulin, glucagon, and liver and adipose tissue lipogenic enzymes were measured in tumor-bearing and control rats after 6, 12, 18, 24, and 32 days of tumor growth. Lipoprotein lipase (LPL) activity in heart, soleus muscle, and epididymal fat pads was also determined. On the sixth day, the activity of LPL was reduced in the adipose tissue and remained lower throughout the duration of the experiment. Serum triglycerides were elevated from the 12th day followed by an increase in free fatty acid levels from the 18th day of tumor growth. These changes were accompanied by a decrease in serum insulin levels in the tumor-bearing rats from Day 12. The presence of the tumor also decreased the activities of some of the lipogenic enzymes in liver and adipose tissue, but these changes occurred at the later time points. On the 24th day, a decrease in fat pad weights was found and characterized by a decrease in fat cell size but not in fat cell number. These results suggest that a defect in clearance, due to the decrease in the activity of adipose tissue LPL, may be responsible for the early development of hypertriglyceridemia during tumor growth. In this study, the alterations in the lipogenic enzymes and LPL cannot be attributed to reduced food intake but may be due to the direct or an indirect effect of the tumor on a hormone such as insulin.

Adipose Tissue↗
PubMed1983

Stability of 111In-bleomycin in vivo--properties compared with 57Co-bleomycin.

111Indium-bleomycin (111In-BLM) and 57Co-bleomycin (57Co-BLM) were prepared and their distributions were compared in the tissues, blood, and urine in tumor-bearing and in untreated mice and rats. Autoradiographs of electrophoresis gels showed that patterns for urine from untreated and tumor-bearing animals, collected 1-3 h or 48 h after injection of 111In-BLM were similar to those for in vitro mixtures of urine and 111In-BLM, but differed from the patterns obtained with 111InCl3 under in vivo or in vitro conditions. In rats bearing mammary adenocarcinoma, 48 h after administration of the radiopharmaceutical, the activity ratio of tumor to eleven different tissues was 1.2-4.6 times higher for injected 111In-BLM than for 111InCl3 (P less than or equal to 0.001 or P less than or equal to 0.05). Imaging with a gamma camera depicted tumors in mice more distinctly with 111In-BLM than with 111InCl3. These findings were interpreted as reflecting the stability of 111In-BLM in vivo. The tumor concentration (%dose/g) was higher for the viable area than for the necrotic area for 111In-BLM, but the reverse was true for 57Co-BLM.

Adenocarcinoma↗
PubMed1983

Compensatory hypertrophy of the soleus in tumor-bearing rats.

Compensatory hypertrophy of the rat soleus was compared between normal rats (N) and rats bearing a non-metastasizing mammary tumor (TB). Two weeks after the tumor inoculation, introduced subcutaneously on the midline of the upper back, the two groups of rats underwent unilateral tenotomy of the plantaris and gastrocnemius muscles to induce functional overload or compensatory hypertrophy of the soleus. One week later, the body weight (BW), wet muscle weights (MW), percent of Type I (slow-twitch) and Type II (fast-twitch) muscle fibers and contractile parameters of the isometric twitch (Pt) and tetanic (Po) tensions were evaluated. The TB animals did not show any signs of cancer cachexia. The sham-operated control soleus muscles of the two groups were similar in wet MW, maximum isometric Pt and Po. The latent period (LP), the contraction time (CT), the half relaxation time (HRT) and the number of Type I (slow-twitch) fibers were increased significantly. The hypertrophied muscles in the N and TB rats showed significant declines in the maximum isometric Pt, compared to their respective controls. These data suggest that the compensatory hypertrophy of muscle is expressed similarly in both the normal and tumor-bearing rats but that it interferes with the generation of isometric twitch tension in the muscle.

Adaptation, Physiological↗
PubMed1983

Adjuvant, pulse total parenteral nutrition and tumor response to cycle-specific and cycle-nonspecific chemotherapy.

Previous work has demonstrated that substrate-induced alterations of tumor metabolism can be exploited to enhance tumor response to a cycle-specific chemotherapeutic agent (methotrexate). This study was designed to further investigate the biologic mechanism of this phenomenon by determination of tumor response to additional cycle-specific (Adriamycin) and cycle-nonspecific (Cytoxan) chemotherapeutic agents. Significant potentiation of tumor response during adjuvant total parenteral nutrition (TPN) was observed with methotrexate and Adriamycin but not with Cytoxan. This may imply that tumor sensitization by adjuvant TPN occurs by acceleration of the growth rate of proliferating tumor cells and not by recruitment of dormant tumor cells into the cell cycle.

Adenocarcinoma↗
PubMed1982

Changes in the activities of lipoprotein lipase and the lipogenic enzymes in tumor-bearing rats.

The effects of tumor growth on lipid metabolism were investigated by evaluating serum lipids, lipoprotein lipase activity (LPLA), the lipogenic enzymes, urinary catecholamines along with serum insulin and glucagon levels. We injected 1.5 X 10(6) cells of rat mammary tumor, AC33, and killed the rats on the 18th day. Serum triglycerides and free fatty acids of the tumor-bearing (TB) rats increased 4 and 5 times, respectively, more than the control (C) rats. Total liver lipids were not significantly different between the two groups. Tumor growth produced a 70% decrease in total epididymal fat pad LPLA; there were no changes in soleus muscle LPLA. Serum insulin levels of the TB rats were 49% less than the C rats. The TB rats had significantly lighter epididymal fat pads and lower activities of adipose fatty acid synthetase and citrate cleavage enzyme. Urinary catecholamines of the TB rats were reduced over 30% compared with the C rats. These results show that the hypertriglyceridemia of the TB rats may be due, in part, to a deficiency of adipose tissue LPLA. The data also suggest that the effects of the tumor on lipid metabolism may be mediated through insulin.

Adenocarcinoma↗
PubMed1981

Anti-tumor effect of (S)-10-hydroxycamptothecin on mouse hepatoma BW7756 and its possible mode of action.

(S)-10-Hydroxycamptothecin (OPT), an analog of camptothecin (CPT), was found to inhibit the growth of the mouse hepatoma BW7756, when given at 1.0 mg/kg/day for 14 days. Cell cycle studies using flow cytofluorometry indicated that this drug inhibited the S-Phase of the tumor cells in vivo and the S and G2/M phases in vitro. Similar studies on host liver showed little or no effect. In spite of the narrow range of the effective dose of this drug against mouse hepatoma BW7756, the use of OPT in combination with other antitumor agents may be useful in primary hepatoma or liver metastases in view of its low toxicity towards host liver. A simple cytofluorometric method useful for live cell cycle study has been adapted for this investigation and can be adopted for other drug studies.

Animals↗
PubMed1980

Host-tumor interaction and nutrient supply.

Adequate parenteral nutritional support improves nutritional status in cancer patients, but its effect on tumor growth remains controversial. Using a transplantable mammary adenocarcinoma in a rat-TPN model, the relative effect of different exogenous intravenous nutrients on tumor growth and host maintenance was studied. Relative to chow controls, starvation increased host depletion without reducing tumor growth. Adequate carbohydrate calories alone neither improved host maintenance nor stimulated tumor growth, yet adequate amino acids alone did improve host maintenance but also stimulated tumor growth. Adequate amino acids and carbohydrates given simultaneously maximized both host maintenance and tumor growth. In contrast, an isocaloric, isonitrogenous, intravenous diet providing non-nitrogenous calories as fat promoted host maintenance equivalent to carbohydrate-based TPN with no tumor stimulation. This apparent differential utilization of fat calories by normal and malignant cells may permit manipulation of the relative benefit of parenteral nutrition to host or to tumor, permitting host repletion without tumor stimulation or alternatively tumor stimulation at appropriate times to increase sensitivity to phase-specific antineoplastic therapy.

Adenocarcinoma↗
PubMed1980

Immunity and drug resistance in a mouse glioma.

The failure of chemotherapy often results in the outgrowth of drug-resistant tumor cells, and, since chemotherapy is often combined with immunotherapy, the question arises as to whether immunity directed against the original tumor offers any protection against the drug-resistant tumor cells. To approach this problem, the immunological relationships between a mouse glioma (GL26) and two FUdR-resistant transplantable tumor sublines were studied. Immunity was induced in C57BL/6 mice with neuraminidase-altered GL26 tumor cells. Immunized mice challenged with viable GL26 tumor cells were completely protected, and no tumors grew. Immune mice, when rechallenged with cells from the two FUdR-resistant tumors, gave greater protection against one of the tumors than the other, but not as much as against the original tumor. The results indicate the drug-resistant tumor cells have some immunological properties similar to the original tumor line and that further studies such as these might be of value to the staging of chemoimmunotherapy.

Animals↗
PubMed1979

Effect of nutritional status and 5-fluorouracil on protein synthesis in parenterally alimented LEW/Mai rats.

LEW/Mal rats bearing transplantable adenocarcinomas were maintained parenterally for 4 days on 1) a regimen adequate in amino acids and glucose and 2) severely hypocaloric glucose. Rats from both groups were given 17.5 mg 5-fluorouracil (FUra)/kg/day as a continuous infusion for 3 days. Cumulative nitrogen balance, fractional tissue protein synthesis rates, and liver and muscle distribution of FUra and its metabolites were determined. Results were compared to those found with a series of control rats that were not treated with FUra. No changes attributable to FUra were found in the starved rats (1.25 g glucose/day). In the fed rats (15 g glucose plus 2.5 g amino acids/day), FUra decreased the liver and diaphragm fractional protein synthesis rates and the nitrogen retention.

Adenocarcinoma↗
PubMed1977

The effect of surgical removal of a rat sarcoma on lymphocyte cytotoxicity.

The effect of surgical removal of tumors on cytotoxicity reactions was studied in Lewis-Wister inbred rats bearing a transplantable methylcholanthrene-induced sarcoma (MCI). Lymphocyte cytotoxicity and the effect of the serum in blocking (decreasing) or potentiating (increasing) lymphocyte cytotoxicity were studied using MCI tissue culture cells, prelabeled with 3H-proline, as target cells. After surgical removal of the tumors, tumor nodules were again palpable in all rats by the seventh day after surgery and regrew at an accelerated rate. In control rats bearing the MCI sarcoma, serum blocking activity appeared between the 8th and 13th days and completely inhibited lymphocyte cytotoxicity until death of the animals. Surgical removal of the tumors resulted in a decrease in lymphocyte cytotoxicity and complete absence of serum blocking activity for at least 7 days. By the 13th day, when tumors were again growing rapidly, lymphocyte cytotoxicity had increased markedly, and blocking activity again appeared in the serum.

Animals↗
PubMed1976

5'-nucleotide phosphodiesterase activity of floxuridine-resistant mouse glioma.

In tissue culture experiments, cells derived from glioma 26, a transplantable tumor of C57B1/6 mice, were sensitive to both floxuridine (5-fluorodeoxyuridine) and 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl)phosphate, an enzyme-mediated drug activated by 5'-nucleotide phosphodiesterase. When these compounds were tested on the tumor in animals at a level of 5 mg/kg for 5 days, tumor growth was inhibited approximately 20% by both compounds. When higher levels of 5-fluorodeoxyuridine, 100 mg/kg four times weekly throughout the lifespan of the mouse, were given, the tumor, although inhibited at first, developed resistance and continued to grow until it killed the animal. Phosphodiesterase levels in the tumor rose as the tumor grew. On the other hand, thymidine kinase levels dropped as anticipated from the known 5-fluorodeoxyuridine-resistant hepatoma tissue culture data. This enzyme pattern was maintained in transplantable mouse glioma lines established from the resistant tumors. One of these lines, tested at a level of 5 mg/kg for 5 days, showed no response to 5-fluorodeoxyuridine but was still sensitive to 5-fluorodeoxyuridine-5'-(5-iodo-3-indolyl) phosphate. These experiments, therefore, offer a model system and a rationale for the design and study of more compounds that could be activated by the enzyme phosphodiesterase. Such compounds might be used alternatively when resistance to 5-fluorodeoxyuridine develops, a common clinical experience in the use of this anticancer drug.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1976

Cytotoxicity reactions during immunotherapy of melanoma with neuraminidase altered autologous tumor cells.

Lymphocyte cytotoxicity, serum cytotoxicity, and the ability of the serum to inhibit lymphocyte cytotoxicity (blocking effect) were studied in a melanoma patient treated with six monthly injections of her own (autologous) tumor cells incubated with neuraminidase to increase their antigenicity. The same tumor cells grown in tissue culture were used as target cells for the cytotoxicity test. Large fluctuations of blocking effect in the serum were found, which correlated with the clinical course of tumor removal, recurrence, and regression. After the fifth injection of autologous tumor cells, the blocking effect disappeared from the serum (unblocking). In general, changes in serum cytotoxicity corresponded with changes in the amount of blocking effect produced by the serum. The results suggest that active immunotherapy may play a role in the prevention of metastases and, that when used within the autologous system, the cytotoxicity test is valuable in studying response to this type of therapy.

Antigens, Neoplasm↗
PubMed1976

Neuraminidase immunotherapy: serum potentiation of lymphocyte cytotoxicity related to immunoglobulin levels.

Seven patients completed couses of immunotherapy using neuraminidase-altered autochthonous cells. Their response to therapy was monitored by a cytotoxicity assay using 3H-proline-tagged tumor cells from the patient's own cultured tumor in a strictly autologous system. Serum effects were measured by exposing the tumor target cells to serum to see whether this impeded (blocked) or augmented (potentiated) lymphocyte cytotoxicity. Three of the seven patients developed increasing degrees of serum blocking effect and all died within six months of completing therapy. Four of the seven showed rapidly decreasing blocking and three eventual potentiation. Three patients are living, improved, and free of evidence of tumor. There was an increase in average serum immunoglobulins in patients developing potentiation, and a decrease in those showing blocking. In any immunotherapy program attention must be given to in vitro monitoring studies, and such studies should include attention to the serum factors influencing host response.

Adult↗
PubMed1976

Tumor-caused changes in host protein synthesis under different dietary situations.

The effect of the AC33 tumor on protein synthesis in Lewis-Wistar rats was investigated under four different dietary regimens. The four diets used were: (a) 1.25 g amino acids plus 12.5 g glucose per day, (b) 1.25 g amino acids, (c) 1.25 g glucose per day, and (d) 12.5 g glucose per day. The rats were maintained on these four diets for 4 days. On the 5th day, 65 to 75 mg 99.2% [15N] glycine were added to the infusate and infused at a constant rate for the next 18 hr. The rats were then sacrificed and the liver, lung, heart, kidney, anterior tibialis muscle, and tumor were rapidly removed and frozen in liquid nitrogen. The rate of protein synthesis for these tissues was calculated from the ratio of 15N in the tissue protein to that in the tissue intracellular fluid. The protein synthesis rates were compared with the values found for a series of nontumor control rats fed the same diets. Relative to the control rats, muscle protein synthesis decreased on Diet 1, and liver protein synthesis increased with the three deficient diets.

Adenocarcinoma↗
PubMed1975

New concepts in the immunotherapy of neoplasms.

Elucidation of immunobiologic mechanisms, both in general and particularly as they relate to tumors, is a relatively new endeavor. Clinical application of immunotherapeutic principles has followed tentatively behind the leading edge of research information. Evaluation of this type of therapy is on-going, and results are quite variable. Certainly the major application of immunotherapy must be as an adjuvant, for it is ineffective, both in research and clinical settings, where there is discernible tumor burden. To be properly utilized, immunotherapy must be properly sequenced and not used with other modalities of therapy in such a way as to render it useless. It must be applied with the realization that its effects might be supportive of tumor growth; therefore, frequent assays of tis effects must be carried out both during and after treatment. At the present time, active nonspecific immunotherapy using BCG and active specific therapy using altered autochthonous cells are most in vogue. This is, however, a rapidly changing field and one can anticipate frequent new directions in therapy.

Humans↗
PubMed1974

Synthesis of 1,N6-etheno-2-aza-adenosine (2-aza-epsilon-adenosine): a new cytotoxic fluorescent nucleoside.

1,N(6)-Etheno-2-aza-adenosine was synthesized by treating 1,N(6)-etheno-adenosine with alkali, followed by nitrosation. The mechanism of formation of this novel nucleoside was elucidated using adenosine tritiated at C-8 and C-2, and was found to deformylate exclusively at C-2. This new 2-aza nucleoside fluoresces at 494 nm when excited at 358 nm. Toxicity study showed the compound is active in a rat mammary tumor tissue culture line, but inactive in HeLa and Glioma 26 tissue culture lines. It was also found to selectively inhibit the thymidine incorporation into DNA in a rat mammary tumor, but exhibits no ill effect on normal proliferative tissue. The reactive intermediate 3-beta-D-ribofuranosyl-4-amino-5-(imidazol-2-yl) imidazole was identified and was found to be an active agent in tissue culture.

Adenosine↗