Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer.

Eisenberger, Mario A.; Sinibaldi, Victoria J.; Reyno, Leonard; Sridhara, Rajeshwari; Jodrell, Duncan I.; Zuhowski, Eleanor G.; Tkaczuk, Katherine H.; Lowitt, Mark H.; Hemady, Ramzi K.; Jacobs, Stephen C.

doi:10.1200/jco.1995.13.9.2174

Cited by 71 publications

(42 citation statements)

References 17 publications

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“…Although the crucial role for purinergic signaling in rodent taste systems is well established, clinical evidence for its role in human gustation is scanty. A clinical study testing the effects of the broad-spectrum P2X receptor antagonist suramin reports taste disturbances in more than two-thirds of the patients tested (37). These data implicate a role for receptors containing the P2X subunit in human taste, but whether disrupted NTPDase2 function in a patient population would lead to similar taste disturbances remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

Role of the ectonucleotidase NTPDase2 in taste bud function

Vandenbeuch

Anderson²,

Parnes³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Taste buds are unusual in requiring ATP as a transmitter to activate sensory nerve fibers. In response to taste stimuli, taste cells release ATP, activating purinergic receptors containing the P2X2 and P2X3 subunits on taste nerves. In turn, the released ATP is hydrolyzed to ADP by a plasma membrane nucleoside triphosphate previously identified as nucleoside triphosphate diphosphohydrolase-2 (NTPDase2). In this paper we investigate the role of this ectonucleotidase in the function of taste buds by examining gene-targeted Entpd2-null mice globally lacking NTPDase2. RT-PCR confirmed the absence of NTPDase2, and ATPase enzyme histochemistry reveals no reaction product in taste buds of knockout mice, suggesting that NTPDase2 is the dominant form in taste buds. RT-PCR and immunocytochemistry demonstrated that in knockout mice all cell types are present in taste buds, even those cells normally expressing NTPDase2. In addition, the overall number and size of taste buds are normal in Entpd2-null mice. Luciferin/luciferase assays of circumvallate tissue of knockout mice detected elevated levels of extracellular ATP. Electrophysiological recordings from two taste nerves, the chorda tympani and glossopharyngeal, revealed depressed responses to all taste stimuli in Entpd2-null mice. Responses were more depressed in the glossopharyngeal nerve than in the chorda tympani nerve and involved all taste qualities; responses in the chorda tympani were more depressed to sweet and umami stimuli than to other qualities. We suggest that the excessive levels of extracellular ATP in the Entpd2-knockout animals desensitize the P2X receptors associated with nerve fibers, thereby depressing taste responses.purinergic signaling | synaptic function | E-NTPDase | mouse | gustatory T aste buds, the sensory end organs of gustation, are unique among the special senses in using ATP as a key transmitter to activate their sensory nerve fibers (1). The gustatory nerves express the purinergic receptor subunits P2X2 and P2X3 (2), which rapidly depolarize the nerve terminal when exposed to ATP. An important feature of neurotransmission is the removal of transmitter from extracellular space to prevent desensitization of the receptors by prolonged exposure to the ligand. In the case of taste buds, removal of ATP is accomplished largely by one of the eight known ectonucleotidases (for a review, see ref.3), nucleoside triphosphate diphosphohydrolase-2 (NTPDase2), a highly specific nucleoside triphosphate diphosphohydrolase (4, 5), which preferentially degrades ATP over ADP (6), (i.e., an ectoATPase, as defined histochemically by specificity for ATP).The NTPDase of taste buds is expressed by only one of the three principal types of cells within the bud. Each taste bud contains an onion-shaped cluster of 50-100 elongate taste cells, comprising morphologically and molecularly distinct cell types (for review, see ref. 7): type I, type II, and type III. The detection and transduction of different tastants is accomplished by type II and type III cells (for review...

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Section: Discussionmentioning

confidence: 99%

Role of the ectonucleotidase NTPDase2 in taste bud function

Vandenbeuch

Anderson²,

Parnes³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Factors intrinsic to the bone marrow such as transferrin also reportedly may interfere with the antiproliferative effect of suramin [17]. Interestingly, a clinical report on phase I and II trials of suramin showed rather good responses of measurable prostatic cancer metastatic sites such as liver, lung, lymph nodes, and skin, but no radiographically and only minimal scintigraphically evident responses by bone metastases [2, 3]. …”

Section: Discussionmentioning

confidence: 99%

“…We have established a model of micrometastases to bone and liver in chick embryos using the hormone-independent cancer cell line PC-3 which consistently produces metastases in bone and liver. We used the model to evaluate suramin, a promising agent against hormone-refractory prostate cancer [2, 3, 4], by means of a quantitative PCR assay for micrometastases [5]. …”

Section: Introductionmentioning

confidence: 99%

A Chick Embryo Model for Metastatic Human Prostate Cancer

Kobayashi

Kawakami²,

Endo³

et al. 1998

European Urology

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“…In vitro studies have confirmed the direct antitumor activity of suramin against prostate cancer, breast cancer, sarcoma and colorectal cancer cell lines [10, 11, 12, 13]. Clinical trials of suramin have reported tumor responses in patients with prostate cancer [14, 15, 16, 17, 18, 19, 20, 21, 22, 23], Kaposi’s sarcoma, non-Hodgkin’s lymphoma, renal cell carcinoma and adrenal carcinoma [9, 23]. …”

Section: Introductionmentioning

confidence: 99%

A Pilot Trial of Suramin in Metastatic Breast Cancer to Assess Antiangiogenic Activity in Individual Patients

et al. 2000

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Suramin is a polysulfonated naphthylurea with multiple potential mechanisms of action against tumors, including the ability to bind growth factors known to promote tumor angiogenesis. Using an established fixed dosing scheme for the administration of suramin in patients, a pilot study was conducted in patients with progressive, metastatic breast cancer. The primary objective of this trial is to define the effect of suramin on the angiogenic activity in individual patients using in vitro laboratory assays. The secondary objective was to assess the antitumor effect of suramin in a population of metastatic breast cancer patients. No objective tumor responses were observed in any of the 9 patients who received treatment with suramin, however 1 patient did maintain stable disease status. The strength of angiogenic activity present in patient samples was assessed by testing patient plasma in the capillary endothelial cell migration assay. Angiogenic activity followed over time was lowest in patients with the highest suramin concentrations and highest in patients with the lowest suramin concentrations. We conclude that it is feasible to continually monitor the activity of antiangiogenic agents in individual patients without relying on clinical tumor response.

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Phase I and clinical evaluation of a pharmacologically guided regimen of suramin in patients with hormone-refractory prostate cancer.

Cited by 71 publications

References 17 publications

Role of the ectonucleotidase NTPDase2 in taste bud function

Role of the ectonucleotidase NTPDase2 in taste bud function

A Chick Embryo Model for Metastatic Human Prostate Cancer

A Pilot Trial of Suramin in Metastatic Breast Cancer to Assess Antiangiogenic Activity in Individual Patients

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