Association of intratumoral pharmacokinetics of fluorouracil with clinical response

Wolf, Walter; Waluch, V.; Presant, Cary A.; Wiseman, Charles L.; Kennedy, Dallas C.; Blayney, Douglas W.; Brechner, R. Ricardo; Kennedy, Peter G. E.

doi:10.1016/s0140-6736(94)92399-x

Cited by 159 publications

(111 citation statements)

References 9 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…At a lower pHe, in which the -ApH is large, such as occurs in solid tumours, there would be an enhancement of 5FU uptake, whereas normal cells (in which ApH is usually positive) will tend to exclude 5FU. In solid tumours this could lead to an accumulation of 5FU relative to other normal tissues, which is precisely what has been recorded in biopsies (Peters et al, 1993) and also by non-invasive '9F MRS in animal models and in the clinic (Findlay et al, 1993;Presant et al, 1994). The hypothesis suggests potential means of manipulating the tumour pH environment for therapeutic gain.…”

Section: Discussionmentioning

confidence: 56%

“…The elimination half-lives (t112) of 5FU in the VX2 tumour of the rabbit , and the Walker 256 adenocarcinoma of the rat (El-Tahtawy and Wolf, 1991), were found to be about 1 h (63-73.2 and 42.2-59.4 min respectively), and greatly exceed the t 12 of 5FU in rat plasma (Au et al, 1983), which is similar to that reported in humans (5-15 min) (Cohen et al, 1982). Presant et al (1994) found that the response of patients to 5FU could be predicted from the rate of loss of tumour 5FU signal, measured by '9F-MRS. These observations suggest that elucidation of the mechanisms by which 5FU accumulates in tumours could be of clinical significance as they may aid the development of more rational combination chemotherapy.…”

mentioning

confidence: 96%

See 1 more Smart Citation

Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells

Ojugo¹,

McSheehy²,

Stubbs³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

Summary To investigate the possible dependence of 5-fluorouracil (5FU) uptake in tumours on the intra-(pH) and extracellular (pH.) pH, a pH gradient (ApH) was imposed across the plasma membrane of ascites tumour cells in vitro, similar to that known to occur in some solid tumours in vivo, by incubation in media of PHe 5-8. A 2:1 (intracellular/extracellular) accumulation of radiolabelled 5FU occurred after 5 min incubation of the cells with 0.5 mm 5FU at pHe of 5.0, 5.5 or 6.0. 5FU metabolism is slow under these conditions, and 5FU uptake was not affected by longer incubations up to 20 min, nor by the absence of a sodium gradient. pHi was estimated from the distribution of the weak acid, (Naguib et al, 1985). 5FU metabolism has been extensively studied by 19F magnetic resonance spectroscopy (MRS) in cultured cells, and in vivo in tumour-bearing animals and patients (for review see Findlay and Leach, 1994). 5FU cytotoxicity is caused by irreversible inhibition of thymidylate synthase (TS) via the generation of the anabolite 5-fluoro-2-deoxyuridine monophosphate (FdUMP) leading to an inhibition of DNA synthesis, and by incorporation of 5-fluorouridine-5-triphosphate (FUTP) into RNA (FU-RNA). The degree of sensitivity to either, or both, of these cytotoxic nucleotides is tissue dependent (Heidelberger et al, 1983). TS inhibition tends to be favoured by prolonged exposure of low 5FU concentrations (approximately 15 giM) for several days, whereas FU-RNA formation tends to be favoured by brief exposures to high concentrations (1 mM) for a few hours (see Aschele et al, 1992). The intracellular concentrations of 5FU and its metabolites are also dependent on the transport and uptake of 5FU into the target cells (Heidelberger et al, 1983).'9F-MRS studies have shown that 5FU appears to be retained longer in tumours than in normal tissues Received 10 March 1997 Revised 11 August 1997 Accepted 20 August 1997 Correspondence to: M Stubbs Guerquin-Kem et al, 1991;Findlay et al, 1993). Enhanced retention has also been shown to be significantly associated with response Findlay et al, 1993), perhaps because higher concentrations of 5FU will sustain its anti-tumour effects by favouring the lasting presence of toxic metabolites at target tissue sites (Peters et al, 1993). The elimination half-lives (t112) of 5FU in the VX2 tumour of the rabbit , and the Walker 256 adenocarcinoma of the rat (El-Tahtawy and Wolf, 1991), were found to be about 1 h (63-73.2 and 42.2-59.4 min respectively), and greatly exceed the t 12 of 5FU in rat plasma (Au et al, 1983), which is similar to that reported in humans (5-15 min) (Cohen et al, 1982). Presant et al (1994) found that the response of patients to 5FU could be predicted from the rate of loss of tumour 5FU signal, measured by '9F-MRS. These observations suggest that elucidation of the mechanisms by which 5FU accumulates in tumours could be of clinical significance as they may aid the development of more rational combination chemotherapy.The pH of tumours measured non-invasively with 31...

show abstract

Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 96%

Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells

Ojugo¹,

McSheehy²,

Stubbs³

et al. 1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…This high intratumoral concentration of 5-FU and its undetectable level in serum could be attributable to the retention ('trapping') of 5-FU in the tumor. Such a 'trapping' of 5-FU within tumor cells has been noted in a number of previous studies of 5-FU therapy 37,38 and has been rationalized on the basis that the 5-FU half-life is significantly longer in tumors than in blood. 37,39 We compared the efficiency of FCU1 gene transfer by MVA vector and nonreplicative-adenovirus, both of which are unable to proliferate in human tumors.…”

Section: Discussionmentioning

confidence: 80%

Modified vaccinia virus Ankara as a vector for suicide gene therapy

et al. 2007

View full text Add to dashboard Cite

Modified vaccinia virus Ankara (MVA) has been used successfully to express various antigens for the development of vaccines. Here we show that MVA can also be used as an efficient vector for the transfer of suicide genes to cancer cells. We have generated a new and highly potent suicide gene, FCU1, which encodes a fusion protein derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We now describe the therapeutic benefit of using MVA to deliver and express the FCU1 gene in cancer cells. MVA-mediated transfer of the FCU1 gene to various human tumor cells results in the production of a bifunctional intracellular enzyme, such that exposure to the prodrug 5-FC suppresses the growth of the tumor cells both in vitro and in vivo. Moreover, we report a more potent tumor growth delay at lower doses of 5-FC using MVA-FCU1 in comparison to adenovirus encoding FCU1. Prolonged therapeutic levels of cytotoxic 5-FU were detected in tumors in mice treated with both MVA-FCU1 and 5-FC while no detectable 5-FU was found in the circulation. This original combination between MVA and FCU1 represents a potentially safe and attractive therapeutic option to test in man.

show abstract

“…Inadequate delivery of macromolecules limits the efficacy of systemic therapies of tumours with cytokines, monoclonal antibodies, and oligonucleotides (Presant et al, 1994;Jain, 1994;1998). One of the major barriers to the delivery is the tumour microvessel wall.…”

mentioning

confidence: 99%

True

et al. 2000

View full text Add to dashboard Cite

Summary Molecular charge is one of the main determinants of transvascular transport. There are, however, no data available on the effect of molecular charge on microvascular permeability of macromolecules in solid tumours. To this end, we measured tumour microvascular permeability to different proteins having similar size but different charge. Measurements were performed in the human colon adenocarcinoma LS174T transplanted in transparent dorsal skinfold chambers in severe combined immunodeficient (SCID) mice. Bovine serum albumin (BSA) and IgG were fluorescently labelled and were either cationized by conjugation with hexamethylenediamine or anionized by succinylation. The molecules were injected i.v. and the fluorescence in tumour tissue was quantified by intravital fluorescence microscopy. The fluorescence intensity and pharmacokinetic data were used to calculate the microvascular permeability. We found that tumour vascular permeability of cationized BSA (pI-range: 8.6-9.1) and IgG (pI: 8.6-9.3) was more than two-fold higher (4.25 and 4.65 × 10 -7 cm s -1 ) than that of the anionized BSA (pI ≈ 2.0) and IgG (pI: 3.0-3.9; 1.11 and 1.93 × 10 -7 cm s -1 , respectively). Our results indicate that positively charged molecules extravasate faster in solid tumours compared to the similar-sized compounds with neutral or negative charges. However, the plasma clearance of cationic molecules was ~2 × faster than that of anionic ones, indicating that the modification of proteins enhances drug delivery to normal organs as well. Therefore, caution should be exercised when such a strategy is used to improve drug and gene delivery to solid tumours.

show abstract

Association of intratumoral pharmacokinetics of fluorouracil with clinical response

Cited by 159 publications

References 9 publications

Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells

Influence of pH on the uptake of 5-fluorouracil into isolated tumour cells

Modified vaccinia virus Ankara as a vector for suicide gene therapy

True

Contact Info

Product

Resources

About