Biomedical subjects

D Kadmon

Publications and source records attributed to D Kadmon.

At least 55 records · Page 3Linked to original sources

PubMed1992

Transforming growth factor beta 1 as a biomarker for prostate cancer.

Using the mouse prostate reconstitution (MPR) model system, under conditions where the ras and myc oncogenes are introduced via a recombinant retrovirus into both the mesenchymal and epithelial compartments of the urogenital sinus, poorly differentiated prostate cancer is produced with high frequency (> 90%) using inbred C57BL/6 mice. Northern blotting and immunohistochemical analysis showed that the transition from benign prostatic hyperplasia (BPH) to prostate cancer is invariably associated with the induction of elevated transforming growth factor-beta 1 (TGF-beta 1) expression. Similar analysis of TGF-beta 1 in human BPH and prostate cancer is consistent with our MPR results and indicates that the accumulation of extracellular TGF-beta 1 is significantly more intense in prostate cancer compared to normal or benign prostate tissues. Interestingly, where benign pathologies are observed in the prostatic stroma in the presence of benign prostatic epithelium, extracellular TGF-beta 1 is seen predominantly in the stromal compartment. Experimental studies clearly demonstrate that mRNA levels of TGF-beta 1 and other growth related genes are regulated by androgens in prostate cancer cells. Overall, our results suggest that elevated TGF-beta 1 is involved in the development of prostate cancer. Direct determination of TGF-beta 1 levels and distribution as well as analysis of localized and systemic effects produced by TGF-beta 1 may serve as useful biomarkers for prostate cancer.

Animals↗

PubMed1992

Chemoprevention in prostate cancer: the role of difluoromethylornithine (DFMO).

The polyamines are normal cell constituents considered to have an important role in the regulation of proliferation and differentiation. DFMO is an irreversible, enzyme-activated, suicide inhibitor of ornithine decarboxylase (ODC), the enzyme responsible for the first and rate-limiting step in mammalian polyamine synthesis. Preliminary data show that DFMO inhibits tumor cell growth in vitro and in vivo, and that it demonstrates chemopreventive activity in a variety of animal tumors. The prostate contains some of the highest concentrations of polyamines and of polyamine-synthetic enzymes (including ODC) in the mammalian organism. ODC activity in the prostate was shown to be more susceptible to DFMO inhibition than in other organs. We have found the ODC activity of the Dunning R3327 rat prostatic carcinomas to be as sensitive to inhibition by DFMO as the normal rat prostate. Furthermore, DFMO was inhibitory to the growth of the tumor both in vitro and in vivo. Given the slow growth rate and long latency period of human prostate cancer and the preliminary DFMO data, we suggest that clinical trials to evaluate the chemopreventive potential of DFMO in prostatic carcinoma deserve serious consideration.

Animals↗

PubMed1992

Alterations in mRNA levels for growth-related genes after transplantation into castrated hosts in oncogene-induced clonal mouse prostate carcinoma.

A clonal mouse prostate carcinoma was established by the introduction of the ras and myc oncogenes via the recombinant retrovirus Zipras/myc 9 using a mouse prostate reconstitution model system. A single-cell suspension derived from an early passage ras+myc-induced carcinoma was inoculated into the flanks of intact or castrated adult male C57BL/6 mice, and tumors were harvested 3 wk postinoculation for northern and Southern blotting. Tumor volume analysis showed that this carcinoma was not dependent on testicular androgens for growth. Southern blot analysis of virus-cell DNA junction fragments revealed that tumor cell populations recovered from both intact and castrated mice were progeny of the same virus-infected cell. Northern blotting showed that mRNA levels for the four growth-related genes transforming growth factor-beta 1 (TGF-beta 1), transforming growth factor-beta 3 (TGF-beta 3), tissue-type plasminogen activator (tPA), and c-myc were significantly elevated in clonal mouse prostate carcinomas grown in castrated hosts. In contrast, androgen receptor mRNA levels were significantly reduced under the same conditions. The response of TGF-beta 1, tPA, and c-myc mRNA levels in the carcinomas grown in castrated hosts was similar to that shown previously in normal rat ventral prostate. However, unlike normal rat ventral prostate after castration, increased numbers of apoptotic cells were not seen in the castrated group relative to the intact group at the time of analysis, indicating that the altered gene expression was not associated with cell death. In addition, testosterone-repressed prostate mRNA number 2 levels, shown previously to be elevated after castration in normal rat ventral prostate, were not increased in the androgen-deprived clonal mouse prostate carcinomas. Therefore, this early passage clonal ras+myc-induced prostate carcinoma demonstrates unique patterns of expression for a set of growth-related genes in an androgen-deprived environment.

Androgens↗

PubMed1992

Androgen sensitivity and gene expression in ras + myc-induced mouse prostate carcinomas.

We established an androgen-sensitive cell line (BR31-5) from a ras + myc-induced mouse prostate carcinoma and used this cell line together with a previously reported transplantable androgen-independent mouse prostate carcinoma to investigate patterns of expression for apoptosis-related genes in an androgen-deprived environment. Single cell suspensions derived from the BR31-5 cell line were inoculated into the flank of intact or castrated adult male C57BL/6 mice and tumors were harvested 12 days post-inoculation for Northern blotting. A transplantable androgen-independent prostate cancer was also inoculated into intact or castrated mice and tumors harvested 21 days later. Tumor volume analyses showed that BR31-5 carcinomas were androgen-sensitive. Northern blotting showed that mRNA levels for two apoptosis-related genes, transforming growth factor-beta 1 and c-myc, were significantly elevated to a similar extent in carcinomas grown in castrated hosts compared to intact hosts for both the androgen-sensitive BR31-5 and androgen-independent carcinomas. Levels of mRNA for tissue type plasminogen activator, shown previously to be elevated in androgen-independent carcinomas following growth in castrates, were also increased in BR31-5 carcinomas under similar androgen-deprived conditions but to a lesser extent. Interestingly, testosterone repressed prostate mRNA No. 2 levels shown previously to be similar in both the intact and castrated groups for androgen-independent carcinomas were significantly increased in the castrated group compared to the intact group for BR31-5 carcinomas. Therefore, specific patterns of expression for apoptosis-related genes may be able to discriminate androgen-sensitive and androgen-independent prostate cancer under androgen-deprived conditions.

Androgens↗

PubMed1991

Elevated plasma chromogranin-A concentrations in prostatic carcinoma.

Chromogranin-A is considered a sensitive immunohistochemical tissue marker in neuroendocrine prostatic carcinoma. We report that the plasma chromogranin-A level was elevated in 48% of 25 patients with stage D2 prostate cancer, and suggest that this marker can be used to monitor the clinical course of these patients.

Aged↗

PubMed1991

BCG and the treatment of superficial bladder cancer.

In this report, we review the evolution of bacillus Calmette-Guérin (BCG) immunotherapy as a legitimate form of treatment in superficial, nonmuscle-invasive bladder cancer. In the US, an estimated 45,000 new cases of bladder cancer are diagnosed each year and the annual death rate approaches 11,000. Approximately 70 percent of these cancers are superficial at the time of initial presentation. The treatment of superficial bladder cancer has three objectives: (1) eradication of existing disease, (2) prophylaxis against tumor recurrence, and (3) prevention of tumor progression (either muscular invasion, metastatic spread, or both). Cystectomy generally is reserved for muscle-invasive disease. Transurethral resection of the bladder tumor is the preferred initial therapy. Intravesical instillations of various chemotherapeutic agents following transurethral resection have been extensively investigated. Some of the common agents used include thiotepa, mitomycin, and doxorubicin. Despite such treatment efforts, however, over 40 percent of patients with superficial bladder cancer experience a recurrence of their tumor within three years. Approximately half of these recurrences either present as less-well-differentiated tumors or have already penetrated into the bladder musculature, metastasized, or both. Since Morales et al. first introduced intravesical BCG vaccine for prophylaxis as well as for treatment of superficial bladder tumors in 1976, support has grown rapidly for its use as an alternative to chemotherapy. When used with prophylactic intent following transurethral resection, recurrence rates are lower than those achieved with other agents. In addition, BCG is emerging as the consensus drug of choice for treating carcinoma in situ of the bladder. The mechanisms by which BCG exerts its antitumor activity remain largely unknown. BCG is thought to stimulate a localized, nonspecific inflammatory response that leads to subsequent shedding of tumor cells. A large body of clinical and experimental data suggest an association between the development of an immunologic response to BCG and successful antitumor activity. No universally accepted therapeutic regimen has been agreed upon. One regimen commonly used consists of an ampul of BCG mixed with 50 mL of NaCl 0.9%, instilled once a week for six weeks and retained for two hours prior to voiding. Maintenance therapy generally consists of intravesical doses given at three-month cycles for at least two years of recurrence-free follow-up. Because BCG is a biologic agent, the commercially available products may differ in weight, colony-forming units per vial, and antigenicity. How these product characteristics affect clinical responsiveness to different strains of BCG remains unanswered.

BCG Vaccine↗

PubMed1991

Elevated transforming growth factor-beta 1 and beta 3 mRNA levels are associated with ras + myc-induced carcinomas in reconstituted mouse prostate: evidence for a paracrine role during progression.

Mouse prostate reconstitution is a useful model for studying the progression of ras + myc-induced carcinomas. When these oncogenes were introduced into both the epithelial and the mesenchymal compartments, poorly differentiated adenocarcinomas resulted. Restricted introduction of both oncogenes into the epithelium produced epithelial hyperplasia. Malignancies were produced in two out of 17 cases of selectively transformed epithelium, suggesting that the hyperplastic condition represents a premalignant phenotype. Restricted introduction of both oncogenes into the mesenchyme produced only mesenchymal dysplasia. Transforming growth factor-beta 1 (TGF-beta 1) and beta 3 (TGF-beta 3) mRNA levels were elevated in the ras + myc-induced carcinomas when compared to the normal controls or to the epithelial hyperplasias. In contrast, TGF-beta 2 mRNA levels were similar in all control and ras + myc-induced carcinomas. Elevated TGF-beta 1 mRNA levels were also found in mesenchymal dysplasia pointing to a potential paracrine activity by the ras + myc transformed mesenchyme. We conclude that elevated TGF-beta 1 and beta 3 are correlated with progression to malignancy and that mesenchyme derived TGF-beta 1 may play an important role in the promotion of ras + myc-induced carcinomas in this model system.

Animals↗

PubMed1991

Experimental oncogene induced prostate cancer.

The mouse prostate reconstitution model exploits the ability of the fetal urogenital sinus to differentiate into a mature prostate when grafted under the renal capsule of an adult isogenic male host. By use of a recombinant retroviral vector, the ras and myc oncogenes are introduced singly or in combination into the fetal urogenital sinus--resulting in distinct phenotypes of prostatic pathology: dysplasia (caused by ras), hyperplasia (caused by myc) and frank carcinomas (caused by a combination of ras+myc). This unique experimental model creates in vivo conditions that mimic the natural initiation and progression of cancer. An expanded MPR protocol allows restricted retrovirus infection of the mesenchyme or epithelial compartments to evaluate paracrine activities. It enables almost unparalleled flexibility in addressing fundamental questions in prostate cancer. We have identified genetic variance in the susceptibility to tumour induction between two different strains of mice (mimicking the observation of racial variability in the predisposition to clinical prostate cancer). The MPR model supports data from other tumour models and implicates TGF-beta 1 and TGF-beta 3 as being strongly associated with tumour progression. Finally, with this model, we have established clonal prostate adenocarcinomas to study directly the affects of castration on gene expression. Not only are TGF-beta 1 and TGF-beta 3 mRNA levels increased in association with malignancy but they are also further enhanced by castration treatment. Based on these experimental studies, we believe that TGF-beta 1 and TGF-beta 3 expression strongly influences the progression of prostate cancer. This information will hopefully impact on the development of more effective therapy for this important malignancy.

Adenocarcinoma↗

PubMed1990

Imaging prostate derived tumors with PET and N-(3-[18F]fluoropropyl)putrescine.

Because of the high uptake of polyamines by the prostate and by prostate derived tumors, polyamines have been considered as potential imaging agents for metastatic prostate cancer. We now report the successful PET imaging of the Dunning R3327H prostatic carcinoma with N-(3-[18F]fluoropropyl)putrescine (FPP), a positron-labeled putrescine analog. Additionally, the biodistribution of FPP in tumor bearing Copenhagen male rats is analyzed. The tumor uptake of FPP was high, and the tumor-to-muscle ratios at 1, 2, 3 and 4.5 h post-injection were 7.2 +/- 1.0, 5.61 +/- 1.65, 4.62 +/- 0.21 and 3.51 +/- 0.91 respectively. The estimated radiation dose for FPP was calculated from rat biodistribution data. The radiation dose estimates suggest that the critical organ, following the administration of FPP, is the upper large intenstine which receives 0.3 rad/mCi administered.

Animals↗

PubMed1989

The role of transrectal ultrasonography in the diagnosis and management of prostatic and seminal vesicle cysts.

Cysts in the region of the prostate and seminal vesicles are interesting because of their differential diagnosis and embryological relevance. We present our experience with 5 cases that include a müllerian duct cyst, diverticulum of the spermatic tract, seminal vesicle cyst and 2 prostatic cysts. Transrectal ultrasonography had a significant role in the diagnostic evaluation of these cysts. Ultrasonographically guided transperineal needle aspiration added significant diagnostic information and might have a therapeutic value. After a review of the literature, we propose an algorithm for the evaluation and management of prostatic and seminal vesicle cysts.

Aged↗

PubMed1989

N-3-[18F]fluoropropylputrescine as potential PET imaging agent for prostate and prostate derived tumors.

A potential PET imagining agent for prostate and prostate derived tumors, N-3-[18F]fluoropropylputrescine, has been prepared. The radiochemical yield was 7-10% at end-of-synthesis (EOS) and the specific activity was greater than 1.1 Ci/mumol (overall synthesis time was 1.5 hr). In vivo biodistribution in mature male rats showed high prostate uptake. In rats that were pretreated with alpha-difluoromethylornithine and dihydrotestosterone propionate, the prostate to muscle ratio and prostate to blood ratio increased significantly. This high target uptake and target to nontarget ratio indicates the potential of this compound as a prostate imaging agent.

Animals↗

PubMed1986

2-[18F]fluoroputrescine: preparation, biodistribution, and mechanism of defluorination.

A new radiolabeled analog of putrescine, 18F labeled 2-fluoroputrescine, has been prepared as a potential in vivo imaging agent for prostate and prostate derived tumors. The radiosynthesis yielded 1.5-4.5 mCi amounts of the 18F labeled putrescine analog (1-3% yields at end-of-synthesis), with specific activities ranging from 0.85-4.3 Ci/mmol, in a synthesis time of 2 h. The in vivo biodistribution in mature male rats showed considerable uptake by the bone, indicating defluorination of the compound. In animals pretreated with aminoguanidine, an inhibitor of diamine oxidase, the enzyme important in the metabolism of putrescine, defluorination was markedly reduced, but uptake by the prostate did not improve. These results suggest the need for development of a 18F labeled analog of putrescine which does not defluorinate in vivo, and which has biological properties similar to putrescine.

Animals↗

PubMed1986

alpha-Difluoromethylornithine enhancement of 14C-putrescine uptake by an androgen-dependent prostatic tumor.

Putrescine is a potential scanning agent for metastases of prostatic carcinoma. We examined the in vivo uptake of [14C]-putrescine by the Dunning R3327H Copenhagen rat prostatic tumor and by other tissues, and conclude that: The uptake of [14C]-putrescine by the tumor was higher than that of the normal dorsolateral prostate, but similar to that of the ventral prostate. Tumor accumulation of [14C]-putrescine was enhanced 38% in intact and 45% in castrated animals by pretreatment with alpha-difluoromethylornithine (DFMO), a polyamine synthesis inhibitor. Further enhancement of tumor uptake (94% in intact and 201% in castrated animals) was achieved by combining DFMO pretreatment with androgen stimulation. Oral administration of methyl-glyoxal bis (guanylhydrazone) (MGBG) increased intestinal uptake of [14C]-putrescine, while oral administration of unlabeled spermine and putrescine decreased it. Dexamethasone decreased the uptake of [14C]-putrescine by the spleen and intestine, but also reduced the prostatic uptake to a considerable extent. These observations are useful for the design of a putrescine-based scan for metastases of prostatic carcinoma.

Adenocarcinoma↗

PubMed1986

Regression of metastatic renal cell carcinoma: a case report and literature review.

The literature provides few examples of regression of documented metastatic renal cell carcinoma. We report a case of cytologically documented pulmonary metastases from a renal cell carcinoma, which resolved following nephrectomy and hormonal therapy. The patient has been followed for 6 years without evidence of recurrence.

Adenocarcinoma↗

PubMed1986

Percutaneous drainage of prostatic abscesses.

Percutaneous catheter drainage of intra-abdominal abscesses currently is a well established technique. We report on 2 anuric patients on maintenance hemodialysis who presented with a prostatic abscess. We elected to use a transperineal, percutaneous drainage technique. Adequate drainage was documented by pelvic computerized tomography scans and followup confirmed satisfactory long-term results.

Abscess↗

PubMed1985

Effect of estrogen and androgen administration on alpha-difluoromethylornithine-enhanced putrescine uptake by the rat prostate.

Radiolabeled putrescine is a potential imaging agent for carcinoma of the prostate. The intrinsically high uptake of putrescine into the rat prostate and prostatic carcinoma can be further stimulated by pretreatment of the animals with alpha-difluoromethylornithine (DFMO) uptake, a polyamine synthesis inhibitor. Pharmacological castration of the animals followed by androgen stimulation and DFMO pretreatment achieved a 30:1 prostate/muscle ratio of 14C-putrescine uptake in elderly rats.

Animals↗

PubMed1985

Synthesis and uptake of no-carrier-added 1-[11C]putrescine into rat prostate.

No carrier-added 1-[11C]putrescine has been prepared using a simple two-step procedure. Radiochemical yields of 1-2% at end-of-synthesis were obtained in a synthesis time of 50-60 min. The in vivo uptake of no carrier-added 1-[11C]putrescine into rat prostate was determined and compared to the uptake of no carrier-added material containing varying amounts of non-radioactive putrescine. The in vivo results indicate that the mechanism of uptake into the prostate is saturable.

Animals↗

PubMed1984

Differential effect of alpha-difluoromethylornithine on the in vivo uptake of 14C-labeled polyamines and methylglyoxal bis(guanylhydrazone) by a rat prostate-derived tumor.

The uptake of exogenously administered radiolabeled polyamines by a rat prostate-derived tumor line, the Dunning R3327 MAT-Lu, and various normal tissues was studied. Pretreatment of tumor cells in vitro with alpha-difluoromethylornithine (DFMO), a polyamine synthesis inhibitor, resulted in a markedly enhanced uptake of both [14C]putrescine and [14 C]spermidine. The in vitro uptake of [14C]putrescine by these cells was effectively inhibited by unlabeled spermine, spermidine, 1,8-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 1,4-diaminopentane, and 1,4-diaminobutane, but less effectively by 1,4-diamino-2,3-butene and 1,4-diamino-2,3-butyne. The diamines, 1,3-diaminopropane and 1,2-diaminoethane, were ineffective in inhibiting [14C]putrescine uptake in vitro into the R3327 MAT-Lu cell line. When tumor-bearing animals were pretreated with DFMO or with DFMO and 5-alpha-dihydrotestosterone propionate, the tumor and prostate uptake of [14C]putrescine and [14C]-cadaverine was enhanced but not substantially increased in other tissues. In contrast to the in vitro results, spermidine and spermine were not enhanced substantially by DFMO pretreatment into any tissue, and their uptake into the tumor actually decreased. Ethylenediamine, which does not utilize the polyamine transport system, did not have its uptake increased into any tissue following DFMO pretreatment. The chemotherapeutic agent, methylglyoxal bis(guanylhydrazone), which utilizes the polyamine transport system for uptake into cells, exhibited uptake behavior different from that of the polyamines. Thus, methylglyoxal bis(guanylhydrazone) uptake into the tumor was not significantly increased or decreased by DFMO or by DFMO + 5-alpha-dihydrotestosterone propionate pretreatment, and only the ventral, but not the dorsal-lateral, lobe of the prostate showed increased uptake of methylglyoxal bis(guanylhydrazone) following DFMO + 5-alpha-dihydrotestosterone propionate pretreatment.

Animals↗