Basic fibroblast growth factor infusion increases tumour vascularity, blood flow and chemotherapy uptake.

Tumour response depends on intratumoural cytotoxic concentration, which varies with tumour vascularity. We determined whether basic fibroblast growth factor (bFGF) infusion increased tumour vascularity, blood flow and cytotoxic drug uptake. The effect of interstitial and systemic bFGF infusion was compared with that of saline-infused controls using animal HSN and K12/TR tumour models.

Effect of manipulation of primary tumour vascularity on metastasis in an adenocarcinoma model.

One explanation for the clinical association between tumour vascularity and probability of metastasis is that increased primary tumour vascularity enhances haematogenous dissemination by offering greater opportunity for tumour cell invasion into the circulation (intravasation). We devised an experimental tumour metastasis model that allowed manipulation of primary tumour vascularity with differential exposure of the primary and metastatic tumour site to angiogenic agents. We used this model to assess the effects of local and systemic increases in the level of the angiogenic agent basic fibroblast growth factor on metastasis.

Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases.

Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied.

Correlation between tumour blood flow and fluorouracil distribution in a hypovascular liver metastasis model.

The poor response of colorectal liver metastases to fluorinated pyrimidine chemotherapy may be due to poor drug penetration into the tumour. Chemotherapy delivered by the blood to well perfused areas of tumour must reach less well perfused areas by diffusion. This study examined the relationship between intratumoural blood flow and drug uptake in a hypovascular liver metastasis animal model.

In vivo hyperpolarized 129Xe NMR spectroscopy in tumors.

The first in vivo hyperpolarized 129Xe NMR study in experimental tumors is presented. Hyperpolarized 129Xe was dissolved in solutions, and was injected intratumorally in GH-3 prolactinomas in rats and RIF-1 fibrosarcomas in mice. The 129Xe NMR spectra and apparent spin-lattice relaxation times in the two tumor types present characteristic differences.

62Cu-PTSM and PET used for the assessment of angiotensin II-induced blood flow changes in patients with colorectal liver metastases.

The aim of this study was to establish a quantitative positron emission tomography (PET) method for investigating angiotensin II (AII)-induced changes in blood flow distribution in the liver. This was in order to evaluate the role of vascular manipulation applied to locoregional chemotherapy treatment in patients with colorectal liver metastases. The tracer selected was copper-62 (II) pyruvaldehyde bis-(N4-methyl)thiosemicarbazone (62Cu-PTSM), which exhibits high first-pass extraction and tissue retention following intra-arterial administration.

Copper bis(diphosphine) complexes: radiopharmaceuticals for the detection of multi-drug resistance in tumours by PET.

Experience with imaging of the multi-drug resistance (MDR) phenotype in tumours using technetium-99m sestamibi, a substrate of the P-glycoprotein (Pgp) transporter, suggests that better quantification of images and separation of MDR from other variables affecting tracer uptake in tumours are required. One approach to these problems is the development of short half-life positron-emitting tracers which are substrates of Pgp. Several lipophilic cationic copper(I) bis(diphosphine) complexes labelled with copper-64 have been synthesised and evaluated in vitro as substrates for Pgp.

Radiolabelled 5'-iodo-2'-deoxyuridine: a promising alternative to [18F]-2-fluoro-2-deoxy-D-glucose for PET studies of early response to anticancer treatment.

We investigated the potential of radiolabelled 5-iodo-2'-deoxyuridine (IUdR) as a pharmacodynamic probe for use with positron emission tomography (PET) in studies of early proliferative response to anticancer treatment. Using the hormone-responsive rat mammary carcinoma OES.HR1, we used a multiple radiotracer method to examine treatment-induced changes in 24 h tumour retention of [131I]IUdR, uptake of [3H]2-deoxy-D-glucose ([3H]DG) together with [99mTc]hexylmethylpropylene amineoxine ([99mTc]HMPAO) uptake as a measure of blood flow.

Metal complexes of bleomycin: evaluation of [Rh-105]-bleomycin for use in targeted radiotherapy.

Bleomycin has been used as a carrier for several radioisotopes; however, its potential for clinical use has been limited either by the in vivo stability of the complexes or the half-life of the isotope used. The chemical, biological, and radiological properties of 105Rhodium appear to make it an ideal choice for targeted radiotherapy. The synthesis and purification of a hereto unreported 105Rhodium-bleomycin (105Rh-BLM) complex is described.

Effect of continuous regional vasoactive agent infusion on liver metastasis blood flow.

Regionally administered vasopressors might increase tumour chemotherapy uptake by differentially constricting normal and tumour blood vessels, leading to a selective increase in blood flow to the tumour. In this study, we compared the effects of the vasopressors angiotensin II, vasopressin and endothelin I and the vasodilator calcitonin gene-related peptide (CGRP) by continuously measuring liver parenchymal and tumour blood flow during a 30-min regional vasoactive infusion in a rat HSN liver metastasis model. Vasopressin and angiotensin II produced a vasoconstriction that decreased despite continued infusion, while endothelin I infusion led to prolonged vasoconstriction with a more gradual onset.

Effect of regional angiotensin II infusion on the relationship between tumour blood flow and fluorouracil uptake in a liver metastasis animal model.

The aim of this study was to assess the relationship between tumour:liver blood flow and 5-fluorouracil (5-FU) uptake ratios in a hypovascular liver metastasis animal model, and examine whether they were similarly affected by a 5 min infusion of angiotension II via the hepatic artery. Tumour:liver blood flow ratio was measured using the isotope tracer 64Copper (II)-pyruvaldehyde bis(n-4 methyl thiosemicarbazone, and 5-FU was tritiated. There was a wide variation in tumour:liver blood flow and 5-FU uptake ratios which could only partly be explained by between animal variation, and was not related either to individual tumour size or overall tumour burden within the liver.

Radioimmunotherapy of breast cancer xenografts with monoclonal antibody ICR12 against c-erbB2 p185: comparison of iodogen and N-succinimidyl 4-methyl-3-(tri-n-butylstannyl)benzoate radioiodination methods.

C-erbB2 p185 is a proto-oncogene product expressed in 25-30% of human invasive breast cancers that is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. It is minimally expressed in normal adult tissues (M. F.

Nitric oxide inhibition sustains vasopressin-induced vasoconstriction.

Hepatic parenchymal vasoconstriction increases cytotoxic drug uptake into hepatic metastases by increasing the tumour to liver blood flow ratio. Prolonged infusion of the vasoconstrictor vasopressin does not result in sustained vasoconstriction, and this may limit the benefit of vasopressin in infusional chemotherapy. We have assessed whether loss of vasopressin-induced vasoconstriction is mediated by nitric oxide.

Pharmacokinetics and biodistribution of radiolabelled idoxifene: prospects for the use of PET in the evaluation of a novel antioestrogen for cancer therapy.

With a view to evaluating the role of PET imaging in the development of new anticancer drugs, we are investigating the novel antioestrogen pyrrolidino-4-iodotamoxifen (idoxifene). [125I]idoxifene and [131I]idoxifene have been produced in no-carrier-added form using a tributyl stannylated precursor, and the bio-distribution and dynamic behaviour of the compound investigated using syngeneic transplantable mammary tumours in the rat. Our findings support the use of PET imaging with 124I to study the clinical pharmacology of idoxifene.

Biodistribution and kinetics of radiolabelled pyrrolidino-4-iodo-tamoxifen: prospects for pharmacokinetic studies using PET.

With a view to evaluating the role of PET imaging in early clinical studies of new anticancer drugs, we are investigating the recently developed antiestrogen compound pyrrolidino-4-iodo-tamoxifen (idoxifene). Preliminary experimental studies have been undertaken using [125,131I]idoxifene, following synthesis of a tributyl-stannyl-idoxifene precursor to facilitate radioiodination. We have investigated the tissue biodistribution and kinetics of [125I]idoxifene following i.

Uptake of radiolabelled tyrosine and iodo-methyl tyrosine in experimental rat tumours: influence of blood flow and tumour growth rate.

Radiolabelled amino acids combined with Positron Emission Tomography (PET) may be useful for delineation of the extent of viable tumour and may also provide a rapid and sensitive indicator of response to therapy. Promising early clinical reports led us to investigate the potential use of the amino acid analogue L-3-iodo-alpha-methyl tyrosine (IMT), which may be radioiodinated with isotopes suitable for PET or conventional single photon imaging. We have studied the biodistribution and kinetics of [125I]IMT using two transplantable tumour systems in hooded rats, and have compared the findings with those using the natural amino acid L-tyrosine (TYR) radiolabelled with tritium.

Tissue blood flow estimation with copper(II)-pyruvaldehyde bis (N-4-methylthiosemicarbazone) and PET.

Copper (II)-pyruvaldehyde bis (N-4-methylthiosemicarbazone) (Cu-PTSM) labelled with 62Cu or 64Cu is currently under investigation as a radiotracer for imaging the distribution of blood flow with positron emission tomography (PET). The application of a simple trapped tracer model in conjunction with tissue uptake and continuous arterial sampling to estimate blood flow has been compared with the 57Co-microsphere method in the rat. After intraventricular injection the cumulative arterial function for 64Cu increased progressively due to the presence of circulating non lipophilic complexes.

Nickel-57-doxorubicin, a potential radiotracer for pharmacokinetic studies using PET: production and radiolabelling.

The clinical use of anthracyclines, such as doxorubicin (DXR), is hampered by tumour development of multidrug resistance (MDR). The drug efflux associated with MDR could be characterised in vivo using Positron Emission Tomography (PET) in conjunction with a suitable radiolabelled drug. We are investigating DXR labelled with the positron emitter 57Ni as a potential analogue of the parent drug.

Evaluation of copper(II)-pyruvaldehyde bis (N-4-methylthiosemicarbazone) for tissue blood flow measurement using a trapped tracer model.

Copper(II)-pyruvaldehyde bis (N-4-methylthiosemicarbazone) (Cu-PTSM) labelled with 62,64Cu is a promising radiotracer for the study of blood flow using positron emission tomography (PET). We have investigated the application of a simple trapped tracer model to measurements of tissue 64Cu-PTSM uptake combined with continuous arterial sampling. A dual-tracer method was used to compare blood flow estimated by 64Cu-PTSM with values derived from measurements using cobalt-57 microspheres in the rat.

Effect of blood perfusion on the ablation of liver parenchyma with high-intensity focused ultrasound.

This paper discusses the effect of blood perfusion on the ablation of rat liver tissue with high-intensity focused ultrasound (HIFU). For this study a practical method has been developed, in which the liver blood flow can be reduced by ligation of the hepatic artery and portal vein. During the treatment the rat liver was mobilized out of the abdomen and the blood flow was measured using both the radioactive microsphere method and a laser Doppler blood-flow monitor.

Uptake and distribution of L-3-[I-125] iodo-alpha-methyl tyrosine in experimental rat tumours: comparison with blood flow and growth rate.

Radiolabelled amino acids combined with positron emission tomography (PET) show promise for the accurate delineation of viable tumour extent and may also provide a rapid and sensitive indicator of response to therapy. We have investigated the potential use of the radioiodinated amino acid analogue L-3-iodo-alpha-methyl tyrosine (IMT) for these purposes using experimental tumours in hooded rats. Preliminary studies using HSN tumours and IMT labelled with iodine-125 demonstrated maximum tumour uptake at 15 min post injection although an improved tumour-to-brain ratio was seen at 24 h due to the relatively poor retention of IMT in normal brain.

The vascularity of cutaneous melanoma: a quantitative histological study of lesions 0.85-1.25 mm in thickness.

The vascularity of 107 primary cutaneous melanomas has been characterized by morphometric histological analysis. The lesions selected for study were of thickness 0.85-1.

Quantitative in vivo measurements of tumor perfusion using rubidium-81 and positron emission tomography.

Rubidium-81 (t1/2 = 4.58 hr) was investigated as a tumor perfusion tracer in the VX2 carcinoma implanted into rabbit thigh muscle using a large-area, multiwire proportional chamber positron emission tomography (PET) system. Perfusion was determined using the arterial reference sample method, and the results from PET imaging were compared with postmortem tissue sampling.

Thermal enhancement of radiation response: a growth delay study on superficial human tumour metastases.

In a quantitative study of 96 nodules in 10 patients, an enhancement of radiation response has been demonstrated following the addition of a single heat treatment 3-4 h after a single dose of radiation. Thermal enhancement ratios ranging from greater than 1.6 to 4.

The rabbit as an experimental model for regional chemotherapy. 1. Intra-arterial hindlimb infusion.

Regional delivery of chemotherapy to a tumour or tumour-bearing region has pharmacokinetic advantages over the systemic route. The applications of an animal model for regional drug delivery are outlined. The technique for intra-arterial infusion in the rabbit hindlimb is described.