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Biomedical subjects

M Rotman

Publications and source records attributed to M Rotman.

At least 91 records · Page 5Linked to original sources
PubMed1992

Potentiation of radiation lethality in mouse melanoma cells by mild hyperthermia and chloroquine.

To test the hypothesis that radiosensitization by combined mild hyperthermia and chloroquine may be increased by the presence of melanin in treated cells, Cloudman melanotic mouse melanoma S91/6 cells, and the amelanotic S91/amel cells were incubated during a 3 h post-irradiation period with 0.03 mM chloroquine at 41 degrees C. A considerable increase in radiation lethality was observed (radiation potentiation factor > 1.6) in both cases. Addition of 0.1 mM isobutyl-methyl xanthine (IBMX), a promoter of melanin synthesis, to the growth medium of S91/6 cells 10 days before irradiation, did not further increase the lethality of radiation followed by combined heat and chloroquine treatment. Under these conditions, toxicity to unirradiated cells was slight. On the other hand, 10 microM chloroquine showed similar toxicity to unirradiated B-16 mouse melanoma cells, but did not increase radiation lethality. Factors other than melanin content therefore play a role in the potentiation of radiation lethality by mild hyperthermia and chloroquine.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Potentiation of radiation lethality in HeLa cells by combined mild hyperthermia and chloroquine.

Evidence is presented for the interaction of X irradiation, slightly toxic levels of chloroquine, and mild hyperthermia in the inactivation of colony-forming ability in asynchronous HeLa cells. A three-way interaction was observed which resulted in the potentiation of radiation-induced lethality. There was little evidence of toxicity in unirradiated cells incubated for 3 h with 0.1 mM chloroquine at either 37 or 41 degrees C. The radiopotentiation factor, which is similar to the dose modification factor, was determined from dose-response curves by relating the reciprocal of the slope (D0) of the reference survival curve to that of the survival curve of cells receiving the combined postirradiation treatment with chloroquine and mild hyperthermia. Radiopotentiation factors larger than 1.7 were obtained irrespective of whether the reference D0's were obtained from survival curves for cells irradiated at 37 degrees C without drug or from cells receiving postirradiation treatment with heat or drug only.

Cell Survival↗
PubMed1991

Locally advanced paranasal sinus and nasopharynx tumors treated with hyperfractionated radiation and concomitant infusion cisplatin.

Fourteen patients with paranasal sinus complex and nasopharynx tumors were treated at State University of New York Health Science Center at Brooklyn (Brooklyn, NY) with a regimen of split-course hyperfractionated radiation (120 cGy/fraction) and concomitant cisplatin infusion (5 to 7 mg/m2/24 hours). All of the patients had T4 tumors or massively recurrent disease with base of skull or facial bone involvement. Twelve patients were treated with curative intent receiving total doses of 6000 to 6960 cGy (modal 6750 cGy), whereas two patients were treated with less than 5000 cGy as palliation. Eleven of the 12 patients (92%) achieved a complete response, and 7 of 12 (58%) are alive at 35 to 72 months (mean, 47 months). Five patients are alive with no evidence of disease, and two with a local recurrence. Three patients died of distant disease, and two died from a local recurrence. When the response to treatment was analyzed based on tumor volume and radiation dose, only two of nine lesions measuring between 4 to 10 cm failed locally. The two palliative patients had almost complete local clearance of the disease but died at 2 and 8 months, respectively. In nine patients, the eye or optic nerve was included in the treatment field and received between 2000 to 6960 cGy. Only one of these nine patients had ophthalmic complication and this was confined to the cornea.

Carcinoma, Adenoid Cystic↗
PubMed1991

Leishmania donovani: characterization of a 38-kDa membrane protein that cross-reacts with the mammalian G-protein transducin.

We investigated the presence in Leishmania donovani promastigotes of proteins with homology to the G-proteins known to mediate signal transduction in other organisms. [alpha 32P]GTP binding experiments revealed the presence in the promastigote membrane of GTP-binding sites with high affinity and specificity. Experiments with antisera directed against mammalian G-proteins showed that the promastigotes possess a 38-kDa protein (p38) which strongly reacts with an antiserum directed against a decapeptide containing the C-terminal sequence of transducin, the G-protein that mediates visual signal transduction. The interaction of p38 with the antiserum is specifically blocked by the decapeptide antigen. p38 is enriched in plasma membranes and is absent in cytosol and in a mitochondria-enriched fraction. p38 was also detected in two other Leishmania species, L. mexicana and L. major. The migration of p38 upon sucrose gradient centrifugation of detergent extract of L. donovani membranes corresponded to Mr of approximately 70,000, indicating that p38 is part of an oligomeric structure. The findings suggest that p38 may be a component of a transmembrane signal transduction system in Leishmania.

Amino Acid Sequence↗
PubMed1991

Estimates of radiation absorbed dose for intraperitoneally administered iodine-131 radiolabeled B72.3 monoclonal antibody in patients with peritoneal carcinomatoses.

Using a newly available model for determining estimates of radiation absorbed dose of radioisotopes administered intraperitoneally, we have calculated absorbed dose to tumor and normal tissues based on a surgically controlled study of radiolabeled antibody distribution. Ten patients with peritoneal carcinomatosis received intraperitoneal injections of the murine monoclonal antibody B72.3 radiolabeled with 131I. Biodistribution studies were performed using nuclear medicine methods until laparotomy at 4-14 days after injection. Surgical biopsies of normal tissues and tumor were obtained. The marrow was predicted to be the critical organ, with maximum tolerated dose [200 rad (2 Gy) to marrow] expected at about 200 mCi (7.4 GBq). In patients with large intraperitoneal tumor deposits, the tumor itself is an important source tissue for radiation exposure to normal tissues. Local "hot-spots" for tumor-absorbed dose were observed, with maximum tumor-absorbed dose calculated at 11,000 rad (11 Gy) per 100 mCi (3.7 GBq) administered intraperitoneal; however, tumor rad dose varied considerably. This may pose serious problems for curative therapy, especially in patients with large tumor burdens.

Absorption↗
PubMed1990

Concomitant continuous infusion chemotherapy and radiation.

Attempts to duplicate the cytotoxic effect of oxygen on radioresistant tissues spurred a search by radiation oncologists for other radiosensitizing techniques. This led to large-scale investigations using neutrons and other heavy particle radiations, hyperthermia, altered fractionation schedules, and the systemic use of the halogenated pyrimidines and the electron-affinic compounds. Unfortunately, the promise that the nitroimidazole compounds would selectively sensitize the radioresistant tumor cells and prove to be an effective systemic agent has not been borne out in clinical trials thus far. Existing pharmokinetic and cytokinetic studies have suggested that continuous infusion chemotherapy given concomitantly (CCIC) with irradiation (RT) acts synergistically, resulting in a significant increase in tumor cell killing. These observations have been supported by clinical research studies treating certain epithelial cancers that have resulted in considerably higher locoregional control rates and improved survival. Although initially used in treatment of only advanced or inoperable epithelial carcinomas, CCIC and RT are now being employed in the treatment of lower staged cancers as an organ-sparing procedure. Carcinoma of the anus treated by anteroposterior (AP) resection alone have reported 5-year survival rates of 30% to 60%. CCIC and RT using 5-fluorouracil (5-FU) and mitomycin C have achieved a local control rate of 90% to 100% and a 5-year survival rate of 80% to 86% with sphincter preservation in 90% of these cases. The 5-year survival rate in advanced urinary bladder carcinoma is 25% to 30% for either radiation or surgery and 42% when combined in a preoperative radiation schedule. Using 5-FU CCIC and RT, the local control rate of transitional cell carcinoma of the bladder has been 71% to 86% with a 5-year survival of 62%. 5-FU CCIC and cisplatin and RT used in the treatment of Stages III and IV carcinoma of the cervix yields a locoregional control of 74% compared with the radiation alone local control of 63% for Stage III and 30% for Stage IV disease. Advanced head and neck and paranasal sinus carcinomas treated by cisplatin CCIC and RT show improved tumor clearance even in the presence of bone destruction. A complete response rate of 87% has been reported with the use of cisplatin CCIC and hyperfractionated radiation. Hyperfractionated radiation also appears to improve the local control of advanced head and neck cancers over patients treated with single fractions of radiation with 66% surviving at 22 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Developmental mechanisms regulating the rapid decrease in a cohesion glycoprotein mRNA in Dictyostelium function primarily at the level of mRNA degradation.

During the morphogenetic program in Dictyostelium discoideum, the transcript of the gene encoding the cohesion glycoprotein gp80 accumulates to a maximum level between 4 and 6 hr, (just prior to the onset of aggregation), remains high between 6 and 10 hr (the ripple to loose aggregate stages), and then decreases to less than 10% of the maximum level between 10 and 12 hr (the tight aggregate stage). The level of gp80 transcript also decreases precipitously at the time of the erasure event in the program of dedifferentiation, or when cAMP is added to a dedifferentiating cell population prior to the erasure event. In the dedifferentiation-defective mutant HI4, the cAMP-stimulated system for rapidly reducing the level of gp80 transcript is intact, but the mechanism functioning at the time of the erasure event is defective, demonstrating that the two reduction mechanisms are dissociable. By comparing the levels of gp80 transcript with the levels of in vitro transcription of the gene in isolated nuclei, it is demonstrated that the rapid reduction of gp80 transcript immediately after aggregation and immediately after addition of 10(-4) M cAMP are the result of increased transcript degradation. The rapid reduction of gp80 transcript at the erasure event may also be due to increased transcript degradation, but transcriptional regulation cannot be completely ruled out in this case.

Cell Adhesion Molecules↗
PubMed1990

Adjunctive radiation after radical hysterectomy in stage IB squamous cell carcinoma of the cervix.

The clinical-pathologic records of 178 women with stage IB squamous cell carcinoma treated by radical hysterectomy and pelvic node dissection were reviewed to assess prognostic factors and outcome in relation to adjunctive pelvic radiation. Among 32 women with pelvic nodes metastases, 19 treated with adjunctive radiation had longer recurrence-free intervals and more extrapelvic metastases than 13 nonirradiated women. However, among irradiated women recurrences were more rapidly fatal, so that the survival of the two groups was similar. Among 54 women with deeply invading (10 mm or more) carcinomas confined to the uterus, 17 with adjunctive radiation had recurrence-free intervals and survivals similar to 37 women without radiation, despite more high-risk factors in the irradiated group. The findings suggest that adjunctive pelvic radiation may control pelvic recurrence but not extend survival.

Carcinoma, Squamous Cell↗
PubMed1990

Preliminary results of concurrent radiotherapy and chemotherapy in advanced cervical carcinoma: a phase I-II prospective intergroup NCOG-RTOG Study.

Thirty-eight patients with advanced carcinoma of the cervix were prospectively treated with a concurrent combination of radiotherapy (RT) and chemotherapy (CT) using the drugs 5-fluorouracil (5FU), mitomycin C and cis-platinum as part of a Northern California Oncology Group (NCOG) and Radiation Therapy Oncology Group (RTOG) intergroup study. RT consisted of 36.00 Gy to the pelvis in 4 weeks followed by a 9.00-Gy parametrial boost. This was followed by two intracavitary applications for a total of 4000 mg hr of radium equivalent when possible. 5FU (1000 mg/m2/24 hr for 96 hr by iv infusion) and mitomycin C (10 mg/m2/iv bolus) were given during the second week of external RT. 5FU (dose as above) and cis-platinum (75 mg/m2/iv over 6 hr) were given during the first intracavitary application. Of 36 patients evaluable for toxicity, 11% had grade 3 nonhematological toxicity and 11% had reversible grade 4 hematological toxicity. There were no toxic deaths. A complete response rate of 62.5% was obtained overall (median survival not reached). This study suggests that this particular combination of RT and CT in advanced cervical carcinoma is effective and well tolerated.

Adult↗
PubMed1990

Treatment of advanced transitional cell carcinoma of the bladder with irradiation and concomitant 5-fluorouracil infusion.

Twenty patients with advanced transitional cell carcinoma of the bladder were treated with radiation and concomitant continuous infusion of 5-fluorouracil with or without Mitomycin. Nineteen of 20 patients were assessed for response. Fourteen of 19 patients (74%) obtained a complete response within 3 to 6 months. An additional three patients (15%) acquired and maintained a complete response after local transurethral resection of the tumor and intravesical chemotherapy, raising the overall complete response (CR) rate to 17/19 (89%). Of the two patients with persistent disease, one is alive and well after salvage cystectomy. Eighteen of 20 patients were evaluated for survival with a median follow-up of 38 months. Seven patients remain alive and well 51 to 78 months, whereas three patients died from intercurrent disease. Eight patients died of either distant metastatic disease (7 patients) or regional disease (1 patient). An adjusted survival calculated by the Life Table Method was 53.6% at 5 years, whereas the overall survival was 39%. The combined modality therapy was well tolerated with no need for treatment interruption or reduction in dose. Late bladder complications include one patient with hemorrhagic cystitis, two patients with dysuria, and two with symptoms of irritable bladder. One patient required a colostomy for a chronic hemorrhagic proctitis. Bladder preservation was achieved in 19/20 patients.

Aged↗
PubMed1990

Prophylactic irradiation of the para-aortic lymph node chain in stage IIB and bulky stage IB carcinoma of the cervix, initial treatment results of RTOG 7920.

From November 1979 to October 1986, 367 patients were entered onto RTOG 7920 and randomized to receive either pelvic irradiation alone or pelvic plus para-aortic radiation. Patients with Stage IIB cervical carcinoma who had not undergone curative surgery and patients with Stages IB and IIA cervical carcinoma who were determined by digital exam to have primary tumors measuring 4 cm or greater in lateral dimension were eligible for this study. Clinically apparent or surgically involved para-aortic nodes were reason for exclusion from the study. Pelvic irradiation consisted of 1.6-1.8 Gy per day for 5 days per week to a total of 40-50 Gy. Para-aortic irradiation delivered 44 to 45 Gy in 1.6-1.8 Gy per day, 5 days per week. Pelvic irradiation was to be completed in 4 1/2 to 6 1/2 weeks and para-aortic irradiation in 4 1/2 to 5 1/2 weeks. Intracavitary brachytherapy delivered a total of 4000-5000 mg hr of radium-equivalents or 30-40 Gy to point A. Patients were stratified prior to random treatment assignment by histology, para-aortic nodal status (negative vs. unevaluated), and FIGO stage. As of June 1, 1989, 30 cases were excluded, including five patients who were inevaluable. Two patients who refused the assigned treatment were also excluded. Therefore, a total of 330 cases were analyzable. At 5 years the estimates of survival, the primary endpoint, for the pelvic only and pelvic plus para-aortic irradiation arms are 55% and 65%, respectively (p = 0.043). Several secondary endpoints were also analyzed. Estimates for loco-regional control at 5 years are, for pelvic irradiation only, 66%, and for pelvic plus para-aortic irradiation, 75% (p = 0.21). Distant metastases are estimated in 32% of pelvic irradiation only patients and 25% of pelvic plus para-aortic irradiation patients at 5 years (p = 0.17). When the first disease failure patterns are examined, more patients fail distally when treated only with pelvic radiation than when using pelvic plus para-aortic fields (p = .04). In analysis of patients with grade 3 (severe), grade 4 (life-threatening), and grade 5 (fatal complications), 8% of the patients in both groups had grade 3 severe complications. In the pelvic plus para-aortic group, 11 patients had grade 4 and 2 had grade 5 complications, whereas 6 had grade 4 and none had grade 5 in the pelvic only treatment group.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1990

Diminished survival of young blacks with adenocarcinoma of the prostate.

The survival rates of 117 black and white patients treated by primary radiation for carcinoma of the prostate at the State University of New York Health Science Center at Brooklyn and Kings County Hospital Center were analyzed according to age and race. In addition, stage, grade, and delay time in seeking medical attention were analyzed. Survival was similar in both young (less than 60 years) and old (greater than or equal to 60 years) patients, with 45% and 41% 5-year-survival rates, respectively. Survival was better in white patients, 48% 5-year survival, than in blacks, 35% 5-year survival. Black patients presented with higher stage disease than whites (p less than 0.01). This trend was even greater in young black males, who had higher grade (64% versus 11%; p less than 0.04) and higher stage tumors (p less than 0.05). In addition, young blacks delayed seeking medical attention greater than 3 months 72% of the time, as compared to 0% in white young males (p less than 0.005). A survival difference was also seen in young blacks as compared with young whites: 3.9-year median survival versus 6.0-year median survival, respectively.

Black or African American↗
PubMed1990

Solitary brain metastasis: results of an RTOG/SWOG protocol evaluation surgery + RT versus RT alone.

From 1983 through 1986, the Southwest Oncology Group and Radiation Therapy Oncology Group conducted an intergroup study designed to evaluate the effectiveness of surgical resection in those patients with solitary central nervous system (CNS) metastases. The study was initially designed as a prospective randomized trial. Because of difficulty accruing patients, the registration format was altered and the patients were placed on study according to physician preference. Ninety-seven patients were registered on study and 80 patients were eventually analyzed. Fifty-five patients underwent radiation therapy alone and 25 patients received surgery and radiation. Fifty-nine percent of those patients undergoing radiation therapy alone improved or stabilized while 79% of those patients undergoing surgery and radiation therapy improved or stabilized. Eventually, 22% of the surgically treated patients failed in the brain while 45% of the patients undergoing radiation therapy exhibited a CNS relapse. Survival was improved when corrected for other prognostic factors in those patients undergoing surgical resection. Although not a prospective randomized trial, this study does suggest an improvement in the survival of a select group of patients able to tolerate neurosurgical resection.

Brain Neoplasms↗
PubMed1989

Dictyostelium erasure mutant HI4 abnormally retains development-specific mRNAs during dedifferentiation.

The Dictyostelium mutant HI4 progresses through morphogenesis normally, but is defective in the reverse program of dedifferentiation. In contrast to dedifferentiating wild-type cells, HI4 cells retain the capacity to rapidly reaggregate well after the "erasure event" employing a nonchemotactic aggregation mechanism involving random collisions and cohesion. They also do not lose contact sites A (gp80) at the prescribed time in the dedifferentiation program. HI4 cells accumulate transcripts of the cysteine protease gene CP2 (formerly referred to as 16G1) and the cohesion glycoprotein gene gp80 at the correct times in the morphogenetic program, but abnormally retain these transcripts at high levels well after the prescribed times at which they are lost in wild-type cells during the reverse program of dedifferentiation. The retention of these mRNAs in HI4 cells after the erasure event is not due to abnormal maintenance of a high level of intracellular cAMP during dedifferentiation. The rapid reduction in the level of gp80 transcript which can be effected by the addition of cAMP prior to the erasure event in wild-type cells is also retained by HI4 cells well after the erasure event. The results suggest that cells possess at least two mechanisms for the reduction of gp80 transcript. One involves the immediate response to cAMP and may function during the forward program of development. The second functions specifically during the reverse program of dedifferentiation. It is this latter, erasure-specific mechanism which is selectively defective in the HI4 variant.

Blotting, Northern↗