PubMed Health⌕ Search

Biomedical subjects

L Heilbrun

Publications and source records attributed to L Heilbrun.

At least 19 recordsLinked to original sources
PubMed1999

Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA.

ErbB-2 is overexpressed in several human cancers and conveys a transforming activity that is dependent on tyrosine kinase activity. Antibodies and T cells to ErbB-2 have been isolated from cancer patients, indicating ErbB-2 as a potential target of active vaccination. In this study, 3 mutant ErbB-2 DNA constructs encoding full-length, ErbB-2 proteins were tested as tumor vaccines. To eliminate tyrosine kinase activity, the ATP binding lysine residue 753 was substituted with alanine by replacing codon AAA with GCA in mutant ErbB-2A. To direct recombinant ErbB-2 to the cytoplasm where major histocompatibility complex (MHC) I peptide processing takes place, the endoplasmic reticulum (ER) signal sequence was deleted in cyt ErbB-2. The third construct cyt ErbB-2A contained cytoplasmic ErbB-2 with the K to A mutation. Expression of recombinant proteins was measured by flow cytometry in transfected murine mammary tumor cell line D2F2. Transmembrane ErbB-2 and ErbB-2A were readily detected. Cytoplasmic ErbB-2 and ErbB-2A were detected only after the transfected cells were incubated overnight with a proteasome inhibitor, indicating prompt degradation upon synthesis. ErbB-2 autophosphorylation was eliminated by the K to A mutation as demonstrated by Western blot analysis. Growth of ErbB-2-positive tumor in BALB/c mice was inhibited after vaccination with ErbB-2 or ErbB-2A, but not with cyt ErbB-2 or cyt ErbB-2A. ErbB-2A that is free of tyrosine kinase activity is a potential candidate for anticancer vaccination. The 3 mutant constructs should be useful tools to delineate the role of individual immune effector cell in ErbB-2-specific antitumor immunity and to develop strategies for enhancing such immunity.

Amino Acid Substitution↗
PubMed1999

Preclinical efficacy of thioxanthone SR271425 against transplanted solid tumors of mouse and human origin.

A highly active and broadly active thioxanthone has been identified: N-[[1-[[2-(Diethylamino)ethyl]amino]-7-methoxy-9-oxo-9H-thioxanthen++ +-4-yl] methylformamide (SR271425, BCN326862, WIN71425). In preclinical testing against a variety of subcutaneously growing solid tumors, the following %T/C and Log10 tumor cell kill (LK) values were obtained: Panc-03 T/C = 0, 5/5 cures; Colon-38 (adv. stage) T/C = 0, 3/5 cures, 4.9 LK; Mam-16/C T/C = 0, 3.5 LK; Mam-17/0 T/C = 0, 2.8 LK; Colon-26 T/C = 0, 1/5 cures, 3.2 LK; Colon-51 T/C = 0, 2.7 LK; Panc-02 T/C = 0, 3.1 LK; B16 Melanoma T/C = 13%, 4.0 LK; Squamous Lung-LC12 (adv. stage) T/C = 14%, 4.9 LK; BG-1 human ovarian T/C = 16%, 1.3 LK; WSU-Brl human breast T/C = 25%, 0.8 LK. The agent was modestly active against doxorubicin (Adr)-resistant solid tumors: Mam-17/AdrT/C =23%, 0.8 LK; and Mam-16/C/Adr T/C = 25%, 1.0 LK, but retained substantial activity against a taxol-resistant tumor: Mam-16/C/taxol T/C = 3%, 2.4 LK. SR271425 was highly active against IV implanted leukemias, L1210 6.3 LK and AML1498 5.3 LK. The agent was equally active both by the IV and oral routes of administration, although requiring approximately 30% higher dose by the oral route. Based on its preclinical antitumor profile, it may be appropriate to evaluate SR271425 in clinical trials.

Animals↗
PubMed1998

Preclinical antitumor efficacy of analogs of XK469: sodium-(2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]propionate.

A series of quinoxaline analogs of the herbicide Assure was found to have selective cytotoxicity for solid tumors of mice in a disk-diffusion-soft-agar-colony-formation-assay compared to L1210 leukemia. Four agents without selective cytotoxicity and 14 agents with selective cytotoxicity were evaluated in vivo for activity against a solid tumor. The four agents without selective cytotoxicity in the disk-assay were inactive in vivo (T/C > 42%). Thirteen of the fourteen agents with selectivity in the disk-assay were active in vivo (T/C < 42%). Five of the agents had curative activity. These five agents had a halogen (F, Cl, Br) in the 7-position (whereas Assure had a CI in the 6 position). All agents with curative activity were either a carboxylic acid, or a derivative thereof, whereas Assure is the ethyl ester of the carboxylic acid. All other structural features were identical between Assure and the curative agents. Assure had no selective cytotoxicity for solid tumors in the disk-assay, and was devoid of antitumor activity. The analog XK469 is in clinical development.

Animals↗
PubMed1997

Outcome of African American men screened for prostate cancer: the Detroit Education and Early Detection Study.

PURPOSE: Will early detection impact on stage of disease and recurrence of prostate cancer in a high risk population? We initiated a community based study to educate and recruit African American men for early diagnosis of prostate cancer, that is the Detroit Education and Early Detection (DEED) study. Our objective was to evaluate our recruitment process for this target population, examine the percentage of organ confined prostate cancer in men undergoing radical prostatectomy and measure recurrence biochemically. MATERIALS AND METHODS: A community based study from February 1993 to February 1995 through the African American churches in metropolitan Detroit was initiated. We compared the early detection group treated with radical prostatectomy to the population presenting to our urological clinic during the same period. We tested and followed 1,105 African American men using the prostate specific antigen blood test. RESULTS: Pathologically organ confined prostate cancer was diagnosed in 11 of 17 men (65%) who underwent radical prostatectomy in the DEED project. Within the clinic population 35% of the African American men were diagnosed with pathologically organ confined prostate cancer. The difference between the 2 populations was statistically significant (p = 0.033). Disease recurred in 1 of 15 (7%) and 39 of 157 (25%) men in the DEED and clinic populations, respectively (p = 0.97). CONCLUSIONS: We demonstrated our ability to recruit African American men into a prostate cancer early detection program. We diagnosed early but clinically significant prostate cancers among African American men with characteristics similar to prostate cancers diagnosed in other early detection studies in which the overwhelming majority of men were white.

Aged↗
PubMed1991

5-Fluorouracil, etoposide, and cisplatin in the management of metastatic non-small cell lung cancer.

Encouraging response rates have been reported in Stage III non-small cell lung cancer when 5-fluorouracil (5-FU), etoposide (VP-16), and cisplatin (FED) have been combined with radiation therapy (RT) or RT and surgery. The current study evaluated the effectiveness of FED chemotherapy in 32 patients with metastatic non-small cell lung cancer. Treatment consisted of 5-FU (800 mg/m2/d) on days 1 to 4 by continuous infusion, intravenous (IV) VP-16 (60 mg/m2) over 1 hour on days 1 to 4, and IV cisplatin (60 mg/m2) over 1 hour on day 1. Treatment cycles were repeated every 28 days as toxicity permitted. Partial responses occurred in 7 of 32 patients (22%; 95% confidence limit [CL] 0.09, 0.40), including 6 of 19 patients (32%) with performance status of 0 or 1, and 1 of 13 patients (8%) with performance status of 2 or 3. The median response duration was 5.0 months. Although toxicity was modest and consisted of primarily hematologic and gastrointestinal side effects, this combination does not appear to provide an advantage over other cisplatin combinations in Stage IV non-small cell lung cancer.

Adult↗
PubMed1990

Flavone acetic acid and plasma protein binding.

Both the capacity of healthy human, cancer patient, and mouse plasma proteins to bind flavone acetic acid (FAA) and the qualitative differences in the plasma protein-binding site were studied. The binding capacity of plasma proteins for FAA was saturated within the therapeutic range in both species. The binding of FAA to plasma protein was significantly greater in both healthy human and cancer patient plasma than in mouse plasma. Plasma from patients with cancer bound on the average less FAA than did healthy patient plasma. The concentration of albumin in the plasma varied between healthy humans, cancer patients, and mice, being 5.3 +/- 0.7, 4.7 +/- 0.8, and 3.9 +/- 0.3 g/100 ml, respectively. The protein binding of FAA was found to be dependent on the plasma albumin concentration, but albumin concentration alone was not adequate for the accurate prediction of the percentage of FAA protein bound. Scatchard plots indicated that healthy human plasma had a greater number of high-affinity binding sites than did mouse plasma. FAA binds at the indolebenzodiazepine binding area on albumin and can be displaced from this site by salicylic acid and clofibric acid, but only at supratherapeutic concentrations. Our results indicate that alterations in plasma albumin could contribute to a variable effect with FAA. Therefore, the influence of serum albumin concentration and the nonlinearity of FAA protein binding should be considered in assessment of the appropriateness of a dose schedule for FAA.

Animals↗
PubMed1989

Cellular DNA content parameters in untreated and recurrent squamous cell cancers of the head and neck.

The presence and degree of DNA aneuploidy as measured by the DNA index (DI) and the S phase fraction (SPF) were determined by flow cytometry in 294 specimens from 237 patients with untreated and recurrent squamous cell carcinomas of the head and neck (SCCHN). A descriptive analysis was performed in which the specimen DNA parameters were correlated with stage, size of primary, degree of lymph node involvement, morphological grade, and treatment status of the corresponding patients. Approximately 70% of the previously untreated specimens contained DNA aneuploid populations (DI greater than 1.10) and three quarters had SPF that were above 15%. There was a strong, direct association between DI and SPF (P less than 0.001). There was no correlation of the presence or degree of DNA aneuploidy with the stage of the tumor or the size of the primary or conventional morphological grade of the tumor. Specimens from patients with recurrent tumors and untreated patients with N3 lymph nodes had significantly lower rates of DNA aneuploidy and mean DI. Serial determinations of DNA aneuploidy in patients with SCCHN undergoing cytotoxic therapy are ongoing and may prove useful in the identification and understanding of resistance and response in this tumor.

Adult↗
PubMed1984

Late mortality after partial gastrectomy.

A 10-year prospective study of Hawaii Japanese males with partial gastrectomy shows that the age-adjusted mortality rates in men with partial gastrectomy were slightly higher than in those with an intact stomach, but the difference failed to achieve statistical significance. This excess of mortality is due, in part, to excess smoking by men who had ulcers of the stomach. Although death due to stroke and lung cancer showed the most substantial deviations from the base population, this can be attributed only in part to the tendency of men with these diseases to be smokers. Other factors, possibly related to nutrition, also contribute to the increased risk of mortality from these diseases. Death from coronary heart disease, an illness with a substantial association with smoking in men with an intact stomach was less frequent in men with gastrectomy but the difference was not statistically significant. It would appear that men with partial gastrectomy had other characteristics that weakened the impact of smoking upon coronary disease risk--low blood pressure, low serum cholesterol, low body weight and increased alcohol consumption.

Aged↗
PubMed1984

The effect of long-distance running upon appendicular bone mineral content.

The bone mineral content (BMC) of the os calcis was measured for a group of 20 male runners at the beginning and the end of a 9-month marathon training program. The participants had no previous running experience. The percent change in bone mineral in the runners was compared with that of a control group of male subjects of the same age range (38-68 yr). The consistent runners showed a significant increase in bone mineral over that of the controls; the increase was not significant for inconsistent runners. The data suggest that those runners with longer, more consistent distances gained more bone mineral than those with shorter, more inconsistent distances.

Adult↗
PubMed1983

Thiazide effect on the mineral content of bone.

The thiazide diuretics are known to cause calcium retention. In order to study the effect of thiazides on bone mineralization, we have measured the mineral content of bone at five sites (the distal radius, the distal ulna, the proximal radius, the proximal ulna, and the os calcis) in 1368 men with a mean age of 68 years, including 323 who were taking thiazides for hypertension. The results were adjusted for age and body-mass index. Thiazide users had significantly more bone mineral content at all five sites than did non-users. Untreated hypertensive patients and persons without hypertension had comparable bone mineral content, indicating that the higher mineral content found among thiazide users is related to the drug and not to the underlying hypertension. These findings suggest the possibility of a preventive or therapeutic role for thiazides in osteoporosis.

Aged↗
PubMed1982

Fecal mutagens in two Japanese populations with different colon cancer risks.

Human feces from 223 Japanese in Hawaii at high risk for colon cancer and feces from 166 Japanese of northern rural Japan at low risk for colon cancer were shown to contain mutagenic activity under five different test conditions. The first assay, using the Ames TA98 and TA100 Salmonella test, detected ether-soluble mutagens in the presence and absence of rat liver microsomes. Of these, the TA98 direct-acting mutagens are present more frequently in the feces of the high-risk population than the low-risk population at a high level of statistical significance (p less than 0.01). TA98 mutagens activated by rat liver microsomes also occur significantly more frequently in the feces of the Japanese from Hawaii (p less than 0.05). Mutagens detected by TA100 in the presence and absence of rat liver microsomes are not commonly found in either Japanese population. The second bacterial test system used to detect fecal mutagens uses Escherichia coli rec-. This system detects water-soluble fecal mutagens which are also present more frequently in the high-risk population than in the low-risk population (p less than 0.05).

Age Factors↗
PubMed1980

Combination chemotherapy, radiotherapy, and BCG immunotherapy in extensive (metastatic) small cell carcinoma of the lung. A Southwest Oncology Group study.

From November 1976 to November 1978, the Southwest Oncology Group treated 254 patients with extensive (metastatic) small cell carcinoma of the lung with combination chemotherapy and radiotherapy with and without BCG immunotherapy. Patients receiving BCG achieved a response rate of 50% versus those patients not receiving BCG of 46% (P = .704). Response duration was 20 weeks for the BCG arms and 23 weeks for the no-BCG arms; survival was 28 weeks for the BCG arms versus 29 weeks for the no-BCG arms. An adverse effect in patients surviving more than one year was detected; those continuing to receive BCG had significantly shorter survival, 60 weeks versus 85 weeks (P = .019). Toxicities of the programs were not affected by the addition of BCG immunotherapy. It appears that BCG immunotherapy has no beneficial effect on response rate or duration of response in programs using chemotherapy and radiotherapy for control of metastatic small cell carcinoma of the lung. In addition, because of the adverse effect on long-term survival, we do not recommend the addition of BCG immunotherapy as a treatment modality in this tumor type.

Antineoplastic Agents↗
PubMed1979

Phase II evaluation of ftorafur in previously untreated colorectal cancer: a Southwest Oncology Group Study.

Eighty-four previously untreated patients with metastatic adenocarcinoma of the large intestine received intravenous ftorafur at a dosage of 2.25 g/m2/day for 5 consecutive days. Courses were repeated every three weeks. Regressions were noted in 9 of 84 treated patients (11%). Median survival for all patients was 32 weeks. Responders survived only 5 weeks longer than nonresponders; 36 vs. 31 weeks. Central nervous system toxicity was a limiting factor occurring in one-third of patients. Ftorafur in a daily X5 schedule appears not to make a significant contribution to the management of disseminated colorectal cancer.

Adenocarcinoma↗
PubMed1979

5 FU infusion with mitomycin-C vs. 5 FU infusion with methyl-CCNU in the treatment of advanced upper gastrointestinal cancer: a Southwest Oncology Group Study.

A randomized trial was conducted by the Southwest Oncology Group (SWOG) in advanced carcinoma of the stomach and pancreas. Patients were assigned to receive monthly 5-fluorouracil 96-hour continuous infusions with either bolus mitomycin-C or oral methyl-CCNU. Mitomycin-C and methyl-CCNU were administered every eight weeks. The 5 FU-mitomycin combination produced a 14% and 22% response rate in disseminated stomach and pancreatic carcinoma, respectively. The combination of infusion 5 FU and methyl-CCNU achieved responses in 9% and 5% of stomach and pancreatic tumors, respectively. There was no significant difference in survival between limbs for either tumor. Median survival in gastric carcinoma on the 5 FU-mitomycin regimen was 25 weeks vs. 18 weeks on the 5 FU-METHYL-CCNU arm. In pancreatic carcinoma median survival on the mitomycin limb was 19 weeks as compared to 17 weeks on the methyl-CCNU program. Leukopenia was greater for the first course on the mitomycin limb. Regression analysis demonstrated that performance status was the most important pretreatment characteristic for predicting survival in both tumors. Neither 5 FU infusion combination appears to significantly alter the dismal prognosis of advanced upper gastrointestinal neoplasms.

Antineoplastic Agents↗
PubMed1978

The effectiveness of prophylactic brain irradiation in small cell carcinoma of the lung: a Southwest Oncology Group study.

Brain involvement in small cell carcinoma of the lung is a common phenomenon occurring in from 29 to 45% of patients. Because of this, it was suggested that prophylactic brain irradiation be made a part of treatment plans for small cell carcinoma. In December 1974, the Southwest Oncology Group (SWOG) began treating patients with combination chemotherapy and irradiation of both the primary lesion and whole brain. In two years, there were 390 patients entered into the study. In patients with extensive disease only 6 of 152 prophylactically irradiated patients developed CNS signs or symptoms of CNS recurrence. In limited disease, 6 of 88 prophylactically treated patients had CNS recurrence and in only 4 was this the site of initial failure. We feel prophylactic brain irradiation in small cell carcinoma of the lung is of benefit.

Brain Neoplasms↗