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Biomedical subjects

M Gutman

Publications and source records attributed to M Gutman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Metastases to the retroperitoneum in patients with extremity soft tissue sarcoma: an unusual metastatic pattern.

BACKGROUND: Extremity soft tissue sarcoma (STS) metastasizes preferentially to the lungs via the hematogenous route. Metastases in extrapulmonary sites such as bone, brain, and subcutaneous tissues are observed less frequently. To the authors' knowledge, limb STS primarily metastasizing to the retroperitoneum has not been described to date. The current study reviews the clinical course, management, and patient prognosis in such a pattern of metastasis. METHODS: Records of patients with retroperitoneal metastases originating from an extremity STS between 1994-1998 were reviewed. Patient demographics, primary tumor site, other tumor sites, local recurrence, distant metastasis, treatment, and survival were analyzed. RESULTS: Ten patients were included in the study. All had primary STS of different histologic types and high histologic grade confined to a lower limb. The retroperitoneal metastases were diagnosed between 6-120 months (mean, 45 months) after diagnosis of the primary sarcoma. At that time, one patient had evidence of local recurrence of the primary tumor site, two patients had lung metastases, and one patient had diffuse bone metastases. Eight patients were eligible for surgery. In six of these patients the metastases were excised completely. The median follow up was 12 months. Of the six patients who underwent complete resection, 3 were alive at last follow-up with no evidence of disease after 12 months, 14 months, and 24 months, respectively. Two patients with recurrent retroperitoneal disease and one patient with retroperitoneal and lung metastases died despite systemic chemotherapy. CONCLUSIONS: Extremity STS can metastasize hematogenously to the retroperitoneum, a fact that mandates a high index of suspicion and abdominal imaging studies during the follow-up of such patients. Retroperitoneal metastases necessitate aggressive surgical resection to enable prolongation of survival.

Adult↗
PubMed2000

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in advanced soft-tissue sarcomas: histopathological considerations.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients. METHODS: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. RESULTS: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size. CONCLUSIONS: This is the first serial histological description of the effects of tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

Adolescent↗
PubMed2000

Gastrointestinal autonomic nerve (GAN) tumor of the rectum.

Gastrointestinal autonomic nerve (GAN) tumor is a relatively newly defined member of the gastrointestinal stromal tumor family, which is a rare group of mesenchymal neoplasms originating in the bowel wall throughout the entire gastrointestinal tract. A thorough search of the literature revealed only one brief mention of this tumor arising in the rectum. We present a full description of such a tumor and summarize the clinical characteristics, therapeutic measures used, biological behavior, and outcome of this unique case.

Autonomic Nervous System Diseases↗
PubMed2000

Clinical clearance of cervical spinal injuries by emergency nurses.

OBJECTIVES: To determine the interrater reliability between emergency nurses and emergency physicians on defined criteria for clinically clearing the cervical spine in blunt trauma patients. METHODS: Blunt trauma patients, 12 years or older, arriving with cervical spinal precautions were prospectively enrolled as a convenience sample. Each member of the emergency physician-nurse pair completed a questionnaire with regard to five criteria for clinically clearing the cervical spine for each patient. Interrater reliability was determined by calculating the kappa statistics for the individual and combined criteria. RESULTS: Physicians and nurses agreed on the presence or absence of the combined criteria in 175 of 211 patients (82.9%; kappa, 0.65). Agreements on individual criteria were as follows: 1) intoxication--203 patients (96.2%; kappa, 0.82); 2) altered consciousness--197 patients (93.4%; kappa, 0.60); 3) neck pain--185 patients (87.7%; kappa, 0.75); 4) distracting injury--160 patients (75.8%; kappa, 0.36); and 5) neurologic deficit--198 patients (93.8%; kappa, 0.45). If disagreements in which the physician would clinically clear the patient but the nurse would not were considered as agreements, then overall agreement would be 198 of 211 patients (93.8%; kappa, 0.88). On the assumption that nurses would assess patients prior to physicians, they would have cleared 35% of the patients before the physicians. However, they would have ordered 12% more radiographs and unsafely clinically cleared 5% of the patients. CONCLUSIONS: The interrater reliability for the combined cervical spinal injury criteria between emergency nurses and physicians was good to excellent. However, with the training given in this study, nurses would order more radiographs than physicians and would unsafely clinically clear cervical spines in some patients.

Adolescent↗
PubMed2000

Kidney allograft outcome in simultaneous pancreas-kidney transplantation.

BACKGROUND: In simultaneous pancreas-kidney transplantation, with both organs coming from the same donor, the addition of a pancreas to the kidney transplant does not jeopardize the kidney allograft outcome despite higher postoperative SPK morbidity. Pancreas allograft outcome has recently improved due to better organ selection and more accurate surgical techniques. OBJECTIVE: To demonstrate the positive impact of SPK on kidney allograft outcome versus kidney transplantation alone in insulin-dependent diabetes mellitus patients with end-stage renal failure. METHODS: We performed 39 consecutive SPKs in 14 female and 25 male IDDM patients with renal failure after an average waiting time of 9 months. Multi-organ donor age was 30 years (range 12-53). The kidneys were transplanted in the left retroperitoneal iliac fossa following completion of the pancreas transplantation; kidney cold ischemia time was 16 +/- 4 hours. Induction anti-rejection therapy was achieved with polyclonal antithymocytic globulin and methylprednisolone, and maintenance immunosuppression by triple drug therapy (prednisone, cyclosporine or tacrolimus, and azathioprine or mycophenolate mofetil). Infection and rejection were closely monitored. RESULTS: All kidney allografts produced immediate urinary output following SPK. Two renal grafts had mild function impairment due to acute tubular damage but recovered after a short delay. Three patients died from myocardial infarction, cerebrovascular event and abdominal sepsis on days 1, 32 and 45 respectively (1 year patient survival 92%). An additional kidney allograft was lost due to a renal artery pseudo-aneurysm requiring nephrectomy on day 26. Nineteen patients (49%) had an early rejection of the kidney that was resistant to pulse-steroid therapy in 6. No kidney graft was lost due to rejection. Patients with acute kidney-pancreas rejection episodes suffered from severe infection, which was the main cause of morbidity with a 55% re-admission rate. Complications of the pancreas allograft included graft pancreatitis and sepsis, leading to a poor kidney outcome with sub-optimal kidney function at 1 year. Kidney graft survival at one year was 89% or 95% after censoring the data for patients who died with functioning grafts. CONCLUSIONS: Eligible IDDM patients with advanced diabetic nephropathy should choose SPK over kidney transplantation alone from either a cadaver or a living source.

Adolescent↗
PubMed2000

The effect of pneumoperitoneum on dissemination and scar implantation of intra-abdominal tumor cells.

PURPOSE: The role of laparoscopy for the treatment of cancer remains controversial, and a particular concern is port site metastases after laparoscopic surgery. Since laparoscopy is being performed with increasing frequency, the question arises as to whether it is a safe oncological procedure. After intraperitoneal inoculation of renal cell carcinoma cells in a mouse model, we compare abdominal wall scar implantation following laparoscopic trocar insertion and pneumoperitoneum with standard laparotomy, and examine the effects on tumor dissemination in the peritoneal cavity. MATERIALS AND METHODS: Following intra-abdominal RENCA cell inoculation, Balb/c mice were randomized into group 1-20 mice that underwent carbon dioxide pneumoperitoneum and telescope trocar insertion, group 2-20 subjected to laparotomy and group 3-10 anesthetized only. All animals were sacrificed 2 weeks after inoculation, and abdominal wall metastases and intraperitoneal tumor distribution were evaluated. RESULTS: Overall, intra-abdominal implantation of inoculated RENCA tumor cells was detected in 15 of 20 animals (75%) in group 1, 14 of 20 (70%) in group 2 and 10 of 10 (100%) in group 3. Wound metastases developed in 46.7% of the mice in group 1 and 50% in group 2. CONCLUSIONS: There was no difference among the groups in the pattern of intraperitoneal tumor implants and scar seeding incidence. Pneumoperitoneum does not facilitate port site metastases.

Abdominal Muscles↗
PubMed1999

Effects of the antiestrogen EM-800 (SCH 57050) and cyclophosphamide alone and in combination on growth of human ZR-75-1 breast cancer xenografts in nude mice.

Human breast cancer proliferates as heterogeneous cell populations that exhibit different sensitivities to therapeutic agents. A logical approach to control these different cancer cell populations is the use of combined treatment with agents that block cell proliferation or induce apoptosis via different mechanisms. We therefore investigated the effect of treatment with the novel pure antiestrogen EM-800, alone or in combination with chemotherapy, on the growth of ZR-75-1 human breast tumors in nude mice, a well-recognized model of human breast cancer. Mice bearing estrone-releasing silastic implants as estrogenic stimulus received EM-800 or cyclophosphamide alone or in combination for 227 days. Cyclophosphamide (256 mg/kg/2 weeks) was administered by i.p. injection in 64 mg/kg fractions over 4 consecutive days with repetition of the cycle every 14 days. EM-800 was administered p.o. once daily at the maximally effective dose of 300 microg/mouse. After 227 days of treatment, average tumor size in mice receiving estrone alone was 192% higher than pretreatment. The average tumor size of mice treated with chemotherapy was reduced by 47%, whereas on the other hand, EM-800 caused a 81% decrease of the value of the same parameter. The combined treatment (EM-800 + cyclophosphamide), on the other hand, resulted in a 95% decrease in tumor size compared with control estrogen alone. In fact, EM-800 alone decreased tumor size to 55% of the value at the start of treatment, whereas the addition of cyclophosphamide to the antiestrogen further decreased tumor size to as low as 15% of the pretreatment value. The combination of EM-800 and cyclophosphamide resulted in 95% of complete or partial responses compared with 61 and 27% with EM-800 and cyclophosphamide alone, respectively. In fact, in the combination therapy group, only one tumor remained stable, while 17 regressed >50% and four disappeared. It is noteworthy that no tumor progressed with EM-800 alone or in combination with cyclophosphamide. The present data show, for the first time, that the addition of cyclophosphamide to a pure antiestrogen used at a maximal dose causes a more potent inhibition of human breast tumor growth, thus suggesting that combined treatment using a maximal dose of a pure antiestrogen and a chemotherapeutic agent(s), two classes of compounds having different mechanisms of action, could further improve breast cancer therapy above the results achieved with a potent and pure antiestrogen alone in estrogen-sensitive breast cancer.

Animals↗
PubMed1999

Effect of combined treatment with the pure antiestrogen EM-800 and radiotherapy on the growth of human ZR-75-1 breast cancer xenografts in nude mice.

Human breast tumors are usually composed of heterogeneous cell populations that exhibit different sensitivities to therapeutic agents. We therefore investigated the effect of treatment with various regimens of the novel pure antiestrogen EM-800, alone or in combination with external beam radiation therapy, on the growth of human ZR-75-1 xenografts in athymic mice. The animals received a maximal dose of EM-800 (300 microg, p.o.) and/or radiotherapy at the dose of 10 Gy. 2.5 Gy fractions were administered over a 9-day period in four sessions of 13.7 min each (250-kilovolt Siemens with 2-mm aluminum filtration at 90 cm from the source origin). EM-800 was administered p.o. once daily, whereas radiotherapy was repeated every 35 days. Tumor size was expressed as a percentage of the initial tumor size, which was assigned a value of 100%. Average tumor size increased by 514% in ovariectomized mice supplemented with estrone alone for 259 days compared with the pretreatment value. Treatment with radiotherapy or EM-800 alone resulted in 11 and 73% decreases in mean tumor size, respectively, whereas combined treatment given simultaneously at the beginning caused a dramatic 98% decrease in tumor size. The start of radiotherapy on day 35 in EM-800-treated mice, or conversely, the start of EM-800 in irradiated mice at the 35-day time interval, resulted in somewhat lower, 88% and 95%, decreases in tumor size, respectively. In animals receiving EM-800 alone, 40% of tumors disappeared, thus indicating a cytotoxic effect caused by the estrogen blockade achieved with the pure antiestrogen. Eighty-six % of the original tumors disappeared under continuous combined treatment. Most importantly, no tumor reappeared under estrogenic stimulation after stopping treatment, thus indicating cure of 86% of the tumors in the group of animals who received the combination therapy. The present data indicate that combined treatment with EM-800 and radiotherapy yields a faster response, a greater decrease in tumor size, and a higher percentage of complete responses or tumor disappearance (cure) than either treatment used alone. The present data also suggest that maximal benefits are achieved when the pure antiestrogen is administered continuously, starting at the same time as radiation therapy and continued without interruption as adjuvant therapy. The present data also clearly show that efficient blockade of estrogens with a potent and pure antiestrogen is not only cytostatic but is cytotoxic and can lead to the disappearance of an important proportion of tumors or cure.

Animals↗
PubMed1999

[Retroperitoneal sarcoma. Treatment of 51 patients].

Soft tissue sarcomas are exceedingly rare, making up less than 1% of all solid malignancies. In the retroperitoneum, they tend to be large when diagnosed and are a therapeutic challenge to the surgical oncologist. Our experience with 51 patients with retroperitoneal sarcomas operated on during the past 4 years is presented. 37 were primary and 26 presented as recurrent tumors. The group included many different histological subtypes, the majority being high grade tumors. Complete resection was achieved in 84%, necessitating extensive surgery, but was not possible in 8 patients (16%) who underwent partial resection or biopsy only. There was 1 perioperative fatality (2%). 18 (35%) suffered complications, all of which were reversible. The estimated 5-year survival in the complete resection group is 40%, while none of those who underwent partial resection survived more than 2 years. There was significantly better survival in patients with primary, low grade sarcomas which were smaller than 8 cm, compared to those with high-grade, recurrent sarcomas larger than 8 cm. Local recurrence developed in 8 patients of the complete resection group (18%), 2 months to 3 years after surgery. These data show that despite the concept of retroperitoneal sarcomas as being aggressive, invasive tumors with a poor prognosis, the prognosis is not unusually bad. With proper surgical technique, resectability may be high, with improved overall survival.

Adult↗
PubMed1999

Anatomic site of primary melanoma is associated with depth of invasion.

BACKGROUND: The prognosis of melanoma is correlated to the stage of the primary lesion. Tumor site has also been implicated, with locations such as the trunk carrying a worse prognosis than others (such as limbs). HYPOTHESIS: To determine if tumor thickness correlates with location in a nonvisible body area. DESIGN AND SETTING: Retrospective medical record review of all patients with stage I melanoma treated in our medical center between 1986 and 1994. Demographic data as well as primary tumor characteristics were recorded. METHODS: The skin's surface was divided into occult and exposed areas. Exposed indicated visible to the patient during routine activities; occult areas included posterior aspect of the neck, back, posterior aspect of the thigh, calf, and plantar region. Data were analyzed for significance using the chi2 test. RESULTS: Of the 178 patients with stage I melanoma analyzed, 51.1% had limb, 35.9% trunk, and 12.9% head and neck lesions. Depth of invasion was less than 0.76 mm in 32.6%, 0.76 to 1.5 mm in 25.2%, and more than 4 mm in 7.9%. In 87 patients the tumor occurred in occult areas and in 91 patients in exposed areas. Comparing the depth of invasion in these 2 groups disclosed that thin (<0.76 mm) melanomas occurred in 20.7% of occult areas compared with 44% of exposed areas (P<.05). Deeper melanomas (>2.50 mm) occurred in 28.7% of occult areas compared with 12.1% of exposed areas (P<.05). CONCLUSIONS: Tumors in less-visible body areas are significantly thicker at the time of diagnosis than those occurring in more highly visible areas. Delayed detection may be responsible for this finding.

Adolescent↗
PubMed1999

Isolated limb perfusion with high-dose tumor necrosis factor alpha and melphalan for Kaposi sarcoma.

BACKGROUND: Although the classic form of Kaposi sarcoma is considered indolent and benign, at times its evolution is more severe, with an acute onset and debilitating complications necessitating aggressive treatment and even amputation. OBJECTIVE: To evaluate the efficacy of hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan as a limb-sparing modality for extensive regional Kaposi sarcoma. SETTING: University hospital and national referral center. PATIENTS: Five patients, aged 60 to 82 years, with extensive, symptomatic, classic Kaposi sarcoma of the lower limb were operated on. All were candidates for amputation owing to debilitating symptoms. INTERVENTIONS: Patients underwent ILP through the iliac (n = 2), femoral (n = 2), and popliteal (n = 1) vessels. Tumor necrosis factor alpha, 4 mg, and melphalan, 1.5 mg/kg body weight, were perfused for an overall time of 90 minutes. The limb was heated to 40 degrees C. Clinical and pathological responses were recorded for all patients after 6 to 8 weeks. RESULTS: The overall response rate was 100%: 1 of 5 patients had complete response and 4 of 5 had partial response. Two patients had progression of disease 2 months after ILP but one of them was asymptomatic and did not require any further treatment. The second patient underwent amputation. Thus, limb preservation was achieved in 80% (4 of 5 patients). Median follow-up was 24 months. There were no deaths associated with treatment or major system complications. Local complications were all reversible. CONCLUSION: These findings suggest that hyperthermic ILP with tumor necrosis factor alpha and melphalan can be considered an effective palliative and limb-sparing treatment modality for extensive Kaposi sarcoma.

Aged↗
PubMed1999

Multifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalan.

BACKGROUND AND OBJECTIVES: The prognosis for recurrent multifocal limb soft tissue sarcoma (STS) is dismal due to systemic spread. However, many of these patients undergo amputation due to ineffective local control. The purpose of the present study was to determine whether isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan permits limb salvage and palliation for such patients. METHODS: Of 53 STS patients treated with hyperthermic ILP with TNF (3-4 mg) and melphalan (1-1.5 mg/kg), 13 (25%) had multifocal STS and were candidates for amputation. RESULTS: The overall response rate was 92% (12/13) with 38% complete response and 54% partial response. Two patients died during the early postoperative period. Limb salvage was achieved in 85% of patients. One patient (8%) had only stable disease and underwent amputation. Local recurrence occurred in 38% but did not result in amputation. CONCLUSIONS: Although the number of patients in this study is too small to allow definitive conclusions, it seems that ILP/TNF offer limb salvage and palliation for recurrent multifocal STS patients.

Adult↗
PubMed1999

Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

BACKGROUND: The management of extensive, recurrent limb desmoid tumors is extremely difficult. The failure of multimodality treatments, such as repeated resections, radiotherapy, systemic chemotherapy, or endocrine manipulations, can end up with multilating surgery or even amputation, similar problems sometimes encountered in soft tissue sarcoma of the limbs. The high rate of limb salvage achieved by isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan for extensive, high-grade soft tissue sarcoma led us to implement this modality in difficult cases of limb desmoids. METHODS: During a 4-year period, 6 patients aged 14 to 52 years were treated. All were significantly symptomatic and candidates for amputation or mutilating surgery. Five had lower and one had upper limb lesions. Two had multifocal disease. At ILP, 3 to 4 mg TNF and 1 to 1.5 mg/kg melphalan were delivered during a 90-minute period. One patient had a double perfusion. All patients underwent definitive resective operation 6 to 8 weeks after perfusion. RESULTS: No systemic complications were observed, and local complications included reversible skin redness and blisters. Response rate was 83% with 33% (2 of 6) complete response and 50% (3 of 6) partial response. In 1 patient less than 50% regression was observed. Limb salvage rate was 100%; even the patient with stabilization of disease could be locally resected. Local recurrence during a follow-up period of 7 to 55 months (median 45 months) occurred in 2 patients at 8 and 24 months, respectively; the first underwent amputation, whereas for the second a wide excision was possible. CONCLUSIONS: ILP with TNF and melphalan can be used as a limb preservation modality in patients with recurrent desmoids and significant symptoms who would otherwise require multilating surgery to control their neoplasm.

Adolescent↗
PubMed1999

Gastrointestinal stromal sarcomas.

BACKGROUND: Gastrointestinal stromal sarcomas are a rare group of malignancies originating in the bowel wall. METHODS: The treatment of 12 patients with gastrointestinal stromal sarcoma who underwent operation between 1994 and 1998 was reviewed. RESULTS: Eight tumours originated in the stomach; others were in the small bowel or rectum. Five of the tumours were of myogenic origin, two were gastrointestinal autonomic nerve tumours, one was a mixed neural-myoid tumour, and four could not be differentiated. Complete resection was possible in ten patients; in two of the ten en bloc resection of adjacent organs was required to ensure adequate margins. The tumours in the remaining two patients were irresectable because of diffuse intra-abdominal metastatic disease. All patients who underwent complete resection were alive after 4-48 (median 14) months. Two of the ten patients developed recurrence, which was reresected completely. The patients with metastatic disease died less than 1 year after operation. CONCLUSION: Aggressive surgical resection, achieving complete resection, can lead to prolongation of life and may be a potential cure for patients with gastrointestinal stromal sarcoma.

Adult↗
PubMed1999

Isolated limb perfusion with tumour necrosis factor-alpha and melphalan for unresectable bone sarcomas of the lower extremity.

AIMS: Isolated limb perfusion (ILP) with recombinant tumour necrosis factor-alpha (rTNF-alpha) and melphalan has recently been reported to induce major tumour responses and permit limb salvage in over 80% of patients with unresectable soft-tissue sarcomas of the extremities. We investigated whether TNF-based ILP could allow limb-sparing surgery in patients with primary, recurrent or metastatic bone sarcoma to the lower extremity who met the criteria for an amputation and had failed or refused chemotherapy. METHODS: From August 1992 to December 1997, we employed ILP with rTNF-alpha and melphalan in 13 patients with unresectable bone sarcoma of the lower extremity, all of whom were candidates for amputation. The aim was to reduce tumour size and allow the performance of a limb-sparing surgery (LSS). RESULTS: Following ILP, none of the patients had severe local toxicity and only one patient experienced significant systemic side-effects. LSS was subsequently performed in nine of the 13 patients. LSS was feasible in an additional three patients but was not performed because of the emergence of diffused metastatic disease. CONCLUSIONS: ILP with rTNF-alpha and melphalan can allow limb salvage in patients wih locally advanced bone sarcomas who had failed standard treatment options. Its potential role in the treatment of unresectable bone sarcomas of the extremities merits further evaluation.

Adolescent↗
PubMed1998

The proton collecting function of the inner surface of cytochrome c oxidase from Rhodobacter sphaeroides.

The experiments presented in this study address the problem of how the cytoplasmic surface (proton-input side) of cytochrome c oxidase interacts with protons in the bulk. For this purpose, the cytoplasmic surface of the enzyme was labeled with a fluorescein (Flu) molecule covalently bound to Cys223 of subunit III. Using the Flu as a proton-sensitive marker on the surface and phiOH as a soluble excited-state proton emitter, the dynamics of the acid-base equilibration between the surface and the bulk was measured in the time-resolved domain. The results were analyzed by using a rigorous kinetic analysis that is based on numeric integration of coupled nonliner differential rate equations in which the rate constants are used as adjustable parameters. The analysis of 11 independent measurements, carried out under various initial conditions, indicated that the protonation of the Flu proceeds through multiple pathways involving diffusion-controlled reactions and proton exchange among surface groups. The surface of the protein carries an efficient system made of carboxylate and histidine moieties that are sufficiently close to each other as to form a proton-collecting antenna. It is the passage of protons among these sites that endows cytochrome c oxidase with the capacity to pick up protons from the buffered cytoplasmic matrix within a time frame compatible with the physiological turnover of the enzyme.

Electron Transport Complex IV↗
PubMed1998

Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

Analysis of Variance↗