In Vivo Therapy of Neoplastic Meningitis with Methotrexate and 5-[<sup>125</sup>I]iodo-2'-deoxyuridine

Kassis, Amin I.; Dahman, Bassam; Adelstein, James S.

doi:10.1080/028418600750063802

Cited by 29 publications

(16 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, investigators have assessed the therapeutic potential of such radionuclides and have shown them to be efficacious in animals bearing ovarian tumors (42, 43), brain tumors (44), s.c. tumors (45), and, recently, spinal cord tumors (46). Despite these positive findings, some investigators have refrained from pursuing the therapeutic potential of Auger-electron-emitting radionuclides, because the short ranges of the emitted electrons (Ϸ99% have a range Ͻ0.5 m) would seem to require the presence of the radionuclide within each and every targeted tumor cell.…”

Section: Waf1mentioning

confidence: 99%

Bystander effect produced by radiolabeled tumor cells in vivo

Xue

Butler

Makrigiorgos

et al. 2002

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

Self Cite

176

107

View full text Add to dashboard Cite

, and (iii) the overall radiation dose deposited by radiolabeled cells in the unlabeled cells within the growing tumor is <10 cGy, we conclude that the results obtained are a consequence of a bystander effect that is generated in vivo by factor(s) present within and͞or released from the 125 IUdR-labeled cells. These in vivo findings significantly impact the current dogma for assessing the therapeutic potential of internally administered radionuclides. They also call for reevaluation of the approaches currently used for estimating the risks to individuals and populations inadvertently exposed internally to radioactivity as well as to patients undergoing routine diagnostic nuclear medical procedures. Studies in recent years have demonstrated that a radiobiologic phenomenon termed the ''bystander effect'' can be observed in mammalian cells grown in vitro. Bystander damage describes biologic effects, originating from irradiated cells, that occur in unirradiated neighboring cells. Several investigators have reported that when ␣-particles traverse a small fraction of a cell population in vitro, lower rates of survival and higher rates of genetic change are observed than those predicted from directionization-only models (1-6). These changes include increased levels of sister chromatid exchanges, mutations, and micronuclei formation, changes in gene expression, and oncogenic transformation. Cell survival is likewise compromised when cells are cocultured with tritiated thymidine-labeled cells (7, 8) and iodine-125 (9). Similarly, the bystander effect has been reported for microcolonies that have been ␥ irradiated (10) and for cells exposed to media from ␥-irradiated cells (10, 11). Evidence from these reports challenges the past half-century's tenet that radiation produces effects only in cells whose DNA has been damaged either through direct ionization or indirectly (for example, through hydroxyl radicals produced in water molecules in the immediate vicinity of the DNA).Whether radiation-induced bystander effects represent a phenomenon that occurs only ex vivo, i.e., are a byproduct of in vitro conditions and manipulations, or whether they are factual in vivo events has not been fully examined. Consequently, the extension of conclusions derived from in vitro studies to the in vivo situation is uncertain. The demonstration of a bystander effect with an in vivo system and the elucidation of the underlying mechanisms of an in vivo bystander effect would go a long way in translating its implications for humans.Recently, Watson et al. (12) demonstrated chromosomal instability in the progeny of unirradiated bone marrow cells mixed with cells exposed ex vivo to neutrons and transplanted into recipient mice. In this novel system, a sex-mismatch transplantation protocol provides a three-way marker system and allows the investigators to distinguish not only host-derived cells from donor-derived cells, but also irradiated donor stemcell-derived cells from nonirradiated donor stem-cell-derived cells. These studies thus provide the...

show abstract

Section: Waf1mentioning

confidence: 99%

Bystander effect produced by radiolabeled tumor cells in vivo

Xue

Butler

Makrigiorgos

et al. 2002

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

Self Cite

176

107

View full text Add to dashboard Cite

show abstract

“…For this reason, we carried out direct intratumoral injection, which would maximize tumor uptake and markedly reduce uptake of N5-2OH by other tissues and organs. and Sahu et al (69) have carried out extensive studies on direct intracerebral administration of 123 I-and 125 I-radiolabeled 5-iodo-2Ј-deoxyuridine for the diagnosis and treatment of brain tumors and leptomeningeal metastases (70). The direct intratumoral (67), intracerebral (68,69), or intrathecal (70) routes have proven to be the most effective for delivering the maximum amounts of 125 I-5-iodo-2Ј-deoxyuridine to the tumor, and it was superior to systemic administration (66).…”

Section: Boron Containing Nucleosides As Delivery Agents For Nctmentioning

confidence: 99%

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Barth¹,

Yang²,

Madhoun³

et al. 2004

Cancer Research

View full text Add to dashboard Cite

The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4 -2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(؉), and a mutant L929 cell line that is thymidine kinase-1(؊). N5-2OH was the least toxic (IC 50 , 43-70 M), and N7 and N7-2OH were the most toxic (IC 50 , 18 -49 M). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 ؎ 2.3 and 2.2 g/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(؊) tumors were 39.8 ؎ 10.8 and 12.4 ؎ 1.6 g/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 g/g, thereby indicating that there was selective retention by the thymidine kinase-1(؉) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.

show abstract

“…Rats treated with cold IUdR survived for 17-24 days whereas tumor bearing animals treated with 125 IUdR survived for significantly longer and 10-20% were cured [31]. Finally, human rhabdomyosarcoma cells were implanted as a model for leptomeningeal metastases [40]. Treatment commencing at 10 days after implant of 5 x 10 6 tumor cells was by intra-thecal injection of 125 IUdR plus MTX over 12 days.…”

Section: Discussionmentioning

confidence: 99%

125I-Iododeoxyuridine for the Treatment of a Brain Tumor Model: Selection of Conditions for Optimal Effectiveness

Lehnert

Li²,

Bump³

et al. 2011

TONMEDJ

View full text Add to dashboard Cite

Abstract:The intent of this study was to optimise conditions for the use of 125 IUdR in the treatment of cancer. The radiopharmaceutical plus a biomodulator, methotrexate (MTX) was delivered by intra-tumoral injection of a thermosensitive hydrogel forming a slow release depot of 125 IUdR and MTX in the tumor.Methods: The C6 rat glioblastoma was implanted intra-cranially. A chitosan polymer was used to formulate a biodegradable and biocompatible implant for controlled intra-tumoral delivery of 125 IUdR plus MTX.Results: Intratumoral implant of hydrogel loaded with 7.0 -7.4 MBq of 125 IUdR resulted in survival of 20% of treated animals to 180 days after tumor implant. Simultaneous delivery of MTX increased the number of rats that were effectively cured, to 40%. Conclusion:Using an injectable thermolabile hydrogel as vehicle for 125 IUdR delivery a higher level of tumor control was achieved in a rat glioma model than had been previously reported.

show abstract

In Vivo Therapy of Neoplastic Meningitis with Methotrexate and 5-[¹²⁵I]iodo-2'-deoxyuridine

Cited by 29 publications

References 19 publications

Bystander effect produced by radiolabeled tumor cells in vivo

Bystander effect produced by radiolabeled tumor cells in vivo

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

125I-Iododeoxyuridine for the Treatment of a Brain Tumor Model: Selection of Conditions for Optimal Effectiveness

Contact Info

Product

Resources

About

In Vivo Therapy of Neoplastic Meningitis with Methotrexate and 5-[125I]iodo-2'-deoxyuridine

Cited by 29 publications

References 19 publications

Bystander effect produced by radiolabeled tumor cells in vivo

Bystander effect produced by radiolabeled tumor cells in vivo

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

125I-Iododeoxyuridine for the Treatment of a Brain Tumor Model: Selection of Conditions for Optimal Effectiveness

Contact Info

Product

Resources

About

In Vivo Therapy of Neoplastic Meningitis with Methotrexate and 5-[¹²⁵I]iodo-2'-deoxyuridine