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Zvi Fuks

Publications and source records attributed to Zvi Fuks.

15 recordsLinked to original sources
PubMed2003

Pharmacologic inactivation of kinase suppressor of ras-1 abrogates Ras-mediated pancreatic cancer.

Inhibition of the kinase suppressor of ras-1 (KSR1) gene by continuous infusion of phosphorothioate antisense oligonucleotides (ODNs) prevented growth of K-Ras-dependent human PANC-1 pancreatic and A549 non-small-cell lung carcinoma xenografts in nude mice, effected regression of established PANC-1 tumors and inhibited A549 lung metastases, all without apparent toxicity. These studies suggest KSR1 antisense ODNs as a treatment for Ras-dependent human malignancies, in particular pancreatic cancer, which lacks effective curative therapy.

Animals↗
PubMed2003

Radiation and ceramide-induced apoptosis.

Ceramide is a sphingolipid that acts as a second messenger in ubiquitous, evolutionarily conserved, signaling systems. Emerging data suggest that radiation acts directly on the plasma membrane of several cell types, activating acid sphingomyelinase, which generates ceramide by enzymatic hydrolysis of sphingomyelin. Ceramide then acts as a second messenger in initiating an apoptotic response via the mitochondrial system. Radiation-induced DNA damage can also initiate ceramide generation by activation of mitochondrial ceramide synthase and de novo synthesis of ceramide. In some cells and tissues, BAX is activated downstream of ceramide, regulating commitment to the apoptotic process via release of mitochondrial cytochrome c. Genetic and pharmacologic studies in vivo showed that radiation targets the acid sphingomyelinase apoptotic system of microvascular endothelial cells in the lungs, intestines and brain, as well as in oocytes, to initiate the pathogenesis of tissue damage. Regulated ceramide metabolism may produce metabolites, such as sphingosine 1-phosphate, shown to signal antiapoptosis, thus controlling the intensity of the apoptotic response and constituting a mechanism for radiation sensitivity or resistance. An improved understanding of this signaling system may offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Animals↗
PubMed2003

Microvascular function regulates intestinal crypt response to radiation.

Recent evidence suggests that microvascular endothelial apoptosis represents the primary lesion in radiation damage to the gastrointestinal (GI) tract. Rescue of endothelium by depletion of acid sphingomyelinase or i.v. treatment with basic fibroblast growth factor (FGF) prevented the lethal GI syndrome in C(57)Bl/6 mice. Here we show that basic FGF increased crypt survival after irradiation by 2-3 fold, with a dose modification factor at D(10) of 1.15 (P < 0.01). Basic FGF inhibited initial crypt damage, assessed by crypt shrinkage at 18-24 h, but did not significantly affect the regeneration of surviving crypts at 3.5 days after irradiation. These data suggest that microvascular function regulates expression of radiation-induced crypt stem cell clonogen damage in the evolution of radiation injury to the GI mucosa.

Animals↗
PubMed2003

Tumor response to radiotherapy regulated by endothelial cell apoptosis.

About 50% of cancer patients receive radiation therapy. Here we investigated the hypothesis that tumor response to radiation is determined not only by tumor cell phenotype but also by microvascular sensitivity. MCA/129 fibrosarcomas and B16F1 melanomas grown in apoptosis-resistant acid sphingomyelinase (asmase)-deficient or Bax-deficient mice displayed markedly reduced baseline microvascular endothelial apoptosis and grew 200 to 400% faster than tumors on wild-type microvasculature. Thus, endothelial apoptosis is a homeostatic factor regulating angiogenesis-dependent tumor growth. Moreover, these tumors exhibited reduced endothelial apoptosis upon irradiation and, unlike tumors in wild-type mice, they were resistant to single-dose radiation up to 20 grays (Gy). These studies indicate that microvascular damage regulates tumor cell response to radiation at the clinically relevant dose range.

Animals↗
PubMed2003

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

Adult↗
PubMed2003

A study of the effects of internal organ motion on dose escalation in conformal prostate treatments.

BACKGROUND AND PURPOSE: To assess the effect of internal organ motion on the dose distributions and biological indices for the target and non-target organs for three different conformal prostate treatment techniques. MATERIALS AND METHODS: We examined three types of treatment plans in 20 patients: (1) a six field plan, with a prescribed dose of 75.6 Gy; (2) the same six field plan to 72 Gy followed by a boost to 81 Gy; and (3) a five field plan with intensity modulated beams delivering 81 Gy. Treatment plans were designed using an initial CT data set (planning) and applied to three subsequent CT scans (treatment). The treatment CT contours were used to represent patient specific organ displacement; in addition, the dose distribution was convolved with a Gaussian distribution to model random setup error. Dose-volume histograms were calculated using an organ deformation model in which the movement between scans of individual points interior to the organs was tracked and the dose accumulated. The tumor control probability (TCP) for the prostate and proximal half of seminal vesicles (clinical target volume, CTV), normal tissue complication probability (NTCP) for the rectum and the percent volume of bladder wall receiving at least 75 Gy were calculated. RESULTS: The patient averaged increase in the planned TCP between plan types 2 and 1 and types 3 and 1 was 9.8% (range 4.9-12.5%) for both, whereas the corresponding increases in treatment TCP were 9.0% (1.3-16%) and 8.1% (-1.3-13.8%). In all patients, plans 2 and 3 (81 Gy) exhibited equal or higher treatment TCP than plan 1 (75.6 Gy). The maximum treatment NTCP for rectum never exceeded the planning constraint and percent volume of bladder wall receiving at least 75 Gy was similar in the planning and treatment scans for all three plans. CONCLUSION: For plans that deliver a uniform prescribed dose to the planning target volume (PTV) (plan 1), current margins are adequate. In plans that further escalate the dose to part of the PTV (plans 2 and 3), in a fraction of the cases the CTV dose increase is less than planned, yet in all cases the TCP values are higher relative to the uniform dose PTV (plan 1). Doses to critical organs remain within the planning criteria.

Humans↗
PubMed2002

IMRT of large fields: whole-abdomen irradiation.

PURPOSE: To assess the feasibility of inverse planning for whole-abdomen intensity-modulated radiation therapy (IMRT) with bone marrow and kidney sparing and to develop approaches to circumventing field size restrictions in the application of whole-abdomen IMRT using dynamic multileaf collimators (DMLC). METHODS AND MATERIALS: The entire peritoneal cavity as derived from serial computerized tomography scans was defined as the gross target volume, whereas the planning target volume (PTV) was defined as the gross target volume plus a 5-mm margin extending 1 cm superiorly and inferiorly. In 10 randomly selected patients, the PTV ranged from 5629 to 12578 cc (median 7935 cc), and the superior-inferior, lateral, and anterior-posterior dimensions of the PTV ranged from 37 to 46 cm (median 42.5 cm), 27 to 33 cm (median 29 cm), and 18 to 23 cm (median 20 cm), respectively. A single isocenter was defined for patients with field length <40 cm. For patients with fields >40 cm, two isocenters were defined: one in the abdominal region, and the other in the pelvis. For IMRT planning, five 15-MV intensity-modulated beams at gantry angles of 180 degrees, 105 degrees, 35 degrees, 325 degrees, and 255 degrees were used. Optimization was designed to spare kidneys and bones. To fully account for the significant scattered dose contributions, an iterative process for dose calculations was implemented in the optimization. To overcome the 15-cm field width limit of our DMLC delivery system, fields with a width >15 cm were split into two or more subfields. To minimize field match errors, adjacent subfields overlapped by at least 2 cm, with intensity "feathering" in the overlap region. For patients with two isocenters, fields were overlapped and feathered in the cephalad-caudad direction by at least 3 cm. For comparison, conventional anterior-posterior/posterior-anterior 6-MV photon beams with posterior kidney blocks at extended distance were also generated for each patient. RESULTS: Treatment plan optimization calculations required 20-80 min on a 500-MHz DEC alpha workstation. Including beam splitting, an average of 16 DMLC beams was used per patient. Delivery of 150 cGy required, on average, 1442 monitor units. For the same dose constraints on the kidneys, whole-abdomen IMRT resulted in significant dose reduction to the bones and improved PTV coverage as compared to conventional treatment. For a prescription dose of 30 Gy, the volume of the pelvic bones receiving more than 21 Gy was reduced on average by almost 60% with IMRT, and the mean dose to all bones was reduced from 24.0 +/- 1.5 Gy to 18.5 +/- 1.0 Gy (p = 0.002). PTV coverage, as measured by V95 (the volume receiving 95% of the prescription dose), improved from 71.7 +/- 4.8% with conventional treatment to 83.5 +/- 3.9% with IMRT (p = 0.002), although small regions of underdose in areas near the kidneys could not be avoided completely. The high-dose regions within the PTV, as measured by D05 (the dose covering 5% of PTV volume), increased slightly from 31.2 +/- 0.6 Gy with conventional treatment to 32.8 +/- 0.2 Gy with IMRT. CONCLUSION: We have developed a process to plan and deliver whole-abdomen IMRT using standard linear accelerators and DMLC. IMRT can achieve better PTV coverage with the same level of kidney sparing and improved sparing of the bone marrow. These methods may be applicable also to other sites requiring large-field irradiation.

Abdomen↗
PubMed2002

High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients.

PURPOSE: To report the acute and late toxicity and preliminary biochemical outcomes in 772 patients with clinically localized prostate cancer treated with high-dose intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: Between April 1996 and January 2001, 772 patients with clinically localized prostate cancer were treated with IMRT. Treatment was planned using an inverse-planning approach, and the desired beam intensity profiles were delivered by dynamic multileaf collimation. A total of 698 patients (90%) were treated to 81.0 Gy, and 74 patients (10%) were treated to 86.4 Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined according to The American Society of Therapeutic Radiation Oncology Consensus Statement. The median follow-up time was 24 months (range: 6-60 months). RESULTS: Thirty-five patients (4.5%) developed acute Grade 2 rectal toxicity, and no patient experienced acute Grade 3 or higher rectal symptoms. Two hundred seventeen patients (28%) developed acute Grade 2 urinary symptoms, and one experienced urinary retention (Grade 3). Eleven patients (1.5%) developed late Grade 2 rectal bleeding. Four patients (0.1%) experienced Grade 3 rectal toxicity requiring either one or more transfusions or a laser cauterization procedure. No Grade 4 rectal complications have been observed. The 3-year actuarial likelihood of >/= late Grade 2 rectal toxicity was 4%. Seventy-two patients (9%) experienced late Grade 2 urinary toxicity, and five (0.5%) developed Grade 3 urinary toxicity (urethral stricture). The 3-year actuarial likelihood of >/= late Grade 2 urinary toxicity was 15%. The 3-year actuarial PSA relapse-free survival rates for favorable, intermediate, and unfavorable risk group patients were 92%, 86%, and 81%, respectively. CONCLUSIONS: These data demonstrate the feasibility of high-dose IMRT in a large number of patients. Acute and late rectal toxicities seem to be significantly reduced compared with what has been observed with conventional three-dimensional conformal radiotherapy techniques. Short-term PSA control rates seem to be at least comparable to those achieved with three-dimensional conformal radiotherapy at similar dose levels. Based on this favorable risk:benefit ratio, IMRT has become the standard mode of conformal treatment delivery for localized prostate cancer at our institution.

Aged↗
PubMed2002

Involvement of membrane signaling in the bystander effect in irradiated cells.

We have shown previously that when confluent cultures of mammalian cells are exposed to very low fluences of alpha particles, fluences whereby only 1-3% of the cell nuclei are traversed by a particle, genetic effects, including specific gene mutations and sister chromatid exchanges, are induced in neighboring, nonirradiated ("bystander") cells (H. Nagasawa and J. B. Little, Cancer Res., 52: 6394-6396, 1992; H. Nagasawa and J. B. Little, Radiat. Res., 152: 552-557, 1999). The present experiments were designed to determine whether signaling pathways arising in the cell membrane may mediate this effect. Cells were irradiated in the presence of Filipin, an agent that disrupts lipid rafts, effectively inhibiting membrane signaling, and the induction of sister chromatid exchange and HPRT mutations by very low fluences of alpha particles (mean doses 0.17-0.5 cGy) was measured. Filipin completely suppressed the induction of both genetic effects in bystander cells. After exposure to 10 cGy, when most mutations occurred in directly irradiated cells, no suppressive effect of Filipin was observed. These results suggest that membrane signaling may play an important role in the bystander effect of radiation. On the other hand, the effects in directly irradiated cells do not appear to be mediated via the cell membrane.

Alpha Particles↗
PubMed2002

Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer.

PURPOSE: To determine the expected time to serum testosterone normalization after short-course neoadjuvant androgen deprivation therapy (NAAD) and three-dimensional conformal radiotherapy for patients with localized prostate cancer and to identify pretreatment predictors that correlated with the time to testosterone normalization. METHODS: Between 1993 and 1999, 88 patients with localized prostate cancer, treated with NAAD and external beam radiotherapy, were prospectively monitored after treatment with sequential testosterone levels. NAAD was administered before and during the entire course of radiotherapy and discontinued at the end of treatment. The median duration of NAAD was 6 months. The actuarial rate of serum testosterone normalization from the end of treatment was evaluated, and the presence or absence of androgen deprivation-related symptoms was correlated with serum testosterone levels. Symptoms assessed included weight gain, loss of libido, breast tenderness, breast enlargement, hot flashes, and fatigue. RESULTS: Serum testosterone levels returned to the normal range in 57 (65%) of the 88 patients and failed to normalize in 31 patients (35%). The median time to normalization was 18.3 months. The actuarial rate of normalization at 3, 6, 12, and 24 months was 10%, 26%, 38%, and 59%, respectively. In a multivariate analysis, a pretreatment testosterone level in the lower range of normal was the only variable that predicted for delayed testosterone normalization after NAAD (p = 0.00047). Among 45 patients with information concerning androgen deprivation-related symptoms recorded 1 year after cessation of NAAD, 24 (53%) had normalized testosterone levels, but in 21 patients (47%), the levels had not yet returned to normal. At 1 year, only 1 (4%) of 24 patients whose testosterone level had returned to normal experienced NAAD-related symptoms compared with 14 (67%) of 21 patients who did not have normal testosterone levels (p <0.001). CONCLUSION: Testosterone levels often remain depressed for extended periods after cessation of short-course NAAD. Lower baseline testosterone levels predict for a delay in testosterone normalization, and the persistence of symptoms related to androgen deprivation correlates with low testosterone levels.

Androgen Antagonists↗
PubMed2002

Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes.

Ceramide is an important cellular lipid involved in signal transduction and the biosynthesis of complex sphingolipids. It can be hydrolyzed into sphingosine, another important signaling lipid, by the activity of ceramidases. Point mutations in the gene (Asah1) encoding one ceramidase, acid ceramidase (AC), lead to the lysosomal storage disorder Farber disease (FD). To investigate the role of AC in mammalian development, we disrupted the mouse gene Asah1 in embryonic stem cells by homologous recombination mediated insertion of an AC targeting vector into the wild-type sequence. Genotype analysis of over 150 offspring or embryos from heterozygous intercrosses revealed an absence of Asah1(-/-) individuals at embryonic day (E) 8.5 or later, although the ratio of wild-type to Asah1(+/-) individuals from these intercrosses was 1:2. Northern blot analysis showed that AC expression was turned on early in development, by E7.0, and continued through at least E17. In contrast, expression of the related lipid hydrolase, acid sphingomyelinase, was shut down by E11. Asah1(+/-) mice survived and lived a normal lifespan, but developed a progressive lipid storage disease in several of their organs, particularly the liver. These histopathological findings in Asah1(+/-) animals correlated with an up to twofold increase in the ceramide content of these tissues and a reduction n AC activity, confirming that the gene insertion event disrupted AC activity and ceramide metabolism. These results provide direct in vivo evidence that normal ceramide metabolism, and AC activity in particular, is essential for mammalian development. The animals and embryos described here should be a valuable resource for investigators studying the role of ceramide in cell growth and development, as well as those interested in the pathogenesis of FD and other sphingolipid storage disorders.

Acid Ceramidase↗
PubMed2002

Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer.

BACKGROUND AND PURPOSE: We fit phenomenological tumor control probability (TCP) models to biopsy outcome after three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer patients to quantify the local dose-response of prostate cancer. MATERIALS AND METHODS: We analyzed the outcome after photon beam 3D-CRT of 103 patients with stage T1c-T3 prostate cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) (prescribed target doses between 64.8 and 81Gy) who had a prostate biopsy performed >or=2.5 years after end of treatment. A univariate logistic regression model based on D(mean) (mean dose in the planning target volume of each patient) was fit to the whole data set and separately to subgroups characterized by low and high values of tumor-related prognostic factors T-stage ( or=T2c), Gleason score ( 6), and pre-treatment prostate-specific antigen (PSA) ( 10 ng/ml). In addition, we evaluated five different classifications of the patients into three risk groups, based on all possible combinations of two or three prognostic factors, and fit bivariate logistic regression models with D(mean) and the risk group category to all patients. Dose-response curves were characterized by TCD(50), the dose to control 50% of the tumors, and gamma(50), the normalized slope of the dose-response curve at TCD(50). RESULTS: D(mean) correlates significantly with biopsy outcome in all patient subgroups and larger values of TCD(50) are observed for patients with unfavorable compared to favorable prognostic factors. For example, TCD(50) for high T-stage patients is 7Gy higher than for low T-stage patients. For all evaluated risk group definitions, D(mean) and the risk group category are independent predictors of biopsy outcome in bivariate analysis. The fit values of TCD(50) show a clear separation of 9-10.6Gy between low and high risk patients. The corresponding dose-response curves are steeper (gamma(50)=3.4-5.2) than those obtained when all patients are analyzed together (gamma(50)=2.9). CONCLUSIONS: Dose-response of prostate cancer, quantified by TCD(50) and gamma(50), varies by prognostic subgroup. Our observations are consistent with the hypothesis that the shallow nature of clinically observed dose-response curves for local control result from a patient population that is a heterogeneous mixture of sub-populations with steeper dose-response curves and varying values of TCD(50). Such results may eventually help to identify patients, based on their individual pre-treatment prognostic factors, that would benefit most from dose-escalation, and to guide dose prescription.

Biopsy↗
PubMed2002

Intensity-modulated radiation therapy for prostate cancer.

Intensity-modulated radiation therapy (IMRT) represents a new paradigm in radiation treatment planning and delivery for treatment of prostate cancer with enormous potential. Preliminary data indicate that this highly conformal treatment technique can effectively reduce acute and late-occurring toxicities, improving the quality of life of the treated patient and serving as the optimal dose escalation tool. IMRT produces radiation distributions capable of delivering different dose prescriptions to multiple target sites, providing a new opportunity for differential dose painting to increase the dose selectively to specific, image-defined regions within the prostate. Clinical trials will be necessary to define more clearly the true extent of improved tumor control and reduction in normal tissue complications with IMRT in the treatment of prostate cancer.

Humans↗
PubMedDate not supplied

Intensity-modulated radiotherapy.

Intensity-modulated radiotherapy represents a recent advancement in conformal radiotherapy. It employs specialized computer-driven technology to generate dose distributions that conform to tumor targets with extremely high precision. Treatment planning is based on inverse planning algorithms and iterative computer-driven optimization to generate treatment fields with varying intensities across the beam section. Combinations of intensity-modulated fields produce custom-tailored conformal dose distributions around the tumor, with steep dose gradients at the transition to adjacent normal tissues. Thus far, data have demonstrated improved precision of tumor targeting in carcinomas of the prostate, head and neck, thyroid, breast, and lung, as well as in gynecologic, brain, and paraspinal tumors and soft tissue sarcomas. In prostate cancer, intensity-modulated radiotherapy has resulted in reduced rectal toxicity and has permitted tumor dose escalation to previously unattainable levels. This experience indicates that intensity-modulated radiotherapy represents a significant advancement in the ability to deliver the high radiation doses that appear to be required to improve the local cure of several types of tumors. The integration of new methods of biologically based imaging into treatment planning is being explored to identify tumor foci with phenotypic expressions of radiation resistance, which would likely require high-dose treatments. Intensity-modulated radiotherapy provides an approach for differential dose painting to selectively increase the dose to specific tumor-bearing regions. The implementation of biologic evaluation of tumor sensitivity, in addition to methods that improve target delineation and dose delivery, represents a new dimension in intensity-modulated radiotherapy research.

Abdominal Neoplasms↗