Preclinical Auger and gamma radiation dosimetry for fluorodeoxyuridine-enhanced tumour proliferation scintigraphy with [123I]iododeoxyuridine.

Animal experiments have shown that short blocking of thymidine (dThd) synthesis with fluorodeoxyuridine (FdUrd) results in significantly increased DNA incorporation of [(125)I]iododeoxyuridine ([(125)I]IdUrd) in tumour and rapidly cycling tissues. Based on these results, we give an Auger and gamma radiation dosimetry estimate for a scintigraphy study in glioblastoma patients using [(123)I]IdUrd. The Auger radiation dosimetry calculated for patients is based on measurement of DNA-incorporated [(125)I]IdUrd in rapidly dividing tissues in nude mice xenografted with human glioblastoma. Further data obtained 0.5, 6 and 24 h after injection of [(125)I]IdUrd allowed calculation of the additional gamma radiation exposure using MIRDOSE3.1. High gradients of radioactivity concentration between dividing and non-dividing tissues were observed 6 and 24 h after injection of [(125)I]IdUrd combined with FdUrd pretreatment. While the estimated Auger radiation absorbed doses of [(123)I]IdUrd in six rapidly cycling normal tissues in patients are low, the equivalent doses become significant with application of the recommended preliminary radiation weighting factor (W(R)) of 20 for stochastic effects of DNA-associated Auger radiation. Using the latter W(R), extrapolation of the animal results to the proposed patient injection with 300 MBq [(123)I]IdUrd combined with FdUrd pretreatment indicates that the effective dose will be 5.42 mSv, including 1.67 mSv from Auger and 3.75 mSv from gamma radiation. The predicted Auger radiation effective dose for patients undergoing [(123)I]IdUrd scintigraphy will be significant if the enhancement of DNA incorporation that is achieved by means of FdUrd pretreatment is similar to that obtained in animals.

Phase I trial of intraperitoneal iododeoxyuridine with and without intravenous high-dose folinic acid in the treatment of advanced malignancies primarily confined to the peritoneal cavity: flow cytometric and pharmacokinetic analysis.

In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: a clinical and pharmacologic analysis.

BACKGROUND: Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). PATIENTS AND METHODS: IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. RESULTS: Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml. CONCLUSIONS: The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.

An improved method for the analysis of sister-chromatid exchange in vivo.

A single injection method of halogenated nucleosides for analysis in vivo of SCE is reported. Halogenated nucleosides were suspended in plant oils, such as peanut oil, and injected into mice subcutaneously. When the dosage of halogenated nucleosides reached 500 mg/kg, satisfactory differential sister chromatid staining of bone marrow cells was obtained. This technique was simple, neither special equipment nor surgical procedure was needed, and the dosage of halogenated nucleosides was relatively low.

Efficacy of BW759 (9-[[2-hydroxy-1(hydroxymethyl)ethoxy]methyl]guanine) against herpes simplex virus type 1 keratitis in rabbits.

A promising new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]-guanine (BW759), which is structurally similar to acyclovir, was tested against acute herpetic keratitis in the rabbit ocular model. Topical 1-0.1% BW759 given 3-5x per day gave beneficial results in that corneal epithelial involvement, conjunctivitis, iritis, and corneal clouding were reduced even when chemotherapy was initiated at 3 days postinoculation. Under the same conditions, topical BW759 therapy gave slightly better results than acyclovir, and both were better than idoxuridine therapy. Mortality rate and colonization of the trigeminal ganglia by HSV-1 were unaffected by BW759 therapy. Duration of virus, shed into the tear film was reduced by BW759.

Treatment of fatal disseminated vaccinia virus infection in immunosuppressed mice.

Studies were performed to compare the therapeutic effectiveness of three antiviral drugs (ARA-A, ARA-C and IDU) on the course of fatal disseminated vaccinia virus infection in immunosuppressed mice. Treatment with ARA-A begun as late as 7 days after virus infection was significantly effective in preventing death; no antiviral effect of the other two drugs was demonstrated.

Enhancement of 5-iododeoxyuridine-induced endogenous C-type virus activation by polycyclic hydrocarbons: apparent lack of parallelism between enhancement and carcinogenicity.

When mouse MLg cells were treated with 3-methylcholanthrene or 7,12-dimethylbenz[alpha]anthracene in the presence of microsomal enzymes and NADPH after 5-iododeoxyuridine (IUDR) treatment, the induction rate of the endogenous C-type virus was increased fivefold to sixfold in comparison with the culture treated with IUDR only. In this reaction, both the microsomal enzymes and NADPH were indispensable. 7,8-Benzoflavone, an inhibitor of the metabolism of hydrocarbons in hamster embryo cultures, inhibited the reaction. For detecting the enhancing activity, the concentration of IUDR for the pretreatment, the concentration of the test products, and the duration of the treatment with the products were important factors. In screening 30 polycyclic hydrocarbons, we were unable to detect a correlation between the in vivo carcinogenicity in the skin and the enhancing activity in the conditions tested.

Recent advances in antiviral therapy.

It has been demonstrated in clinical trials that (1) the antimetabolites Ara A and F3T are both significantly better than IDU in the treatment of many forms of ocular herpes, and (2) they are not significantly different from each other. In preclinical trials, the IDU ocular insert also has shown itself to be significantly better than IDU drop-ointment therapy, while exposing the eye to 40 percent less drug and adding tremendous convenience and ease of compliance by patients to an otherwise difficult medication schedule. Both photodynamic inactivation and cryotherapy have been shown in clinical trials to have notable therapeutic efficacy against herpes, but undesirable and occasionally severe side-effects have slowed down and possibly stopped the further development of these techniques.

Anti-viral treatment of warts.

Several anti-DNA agents have been tested for their value in the treatment of warts in humans. A pilot study was carried out on patients with warts resistant to other forms of treatment. The agents used were hydroxyurea, idoxuridine and photodynamic inactivation. Idoxuridine 20% in a cream base appears to offer some possibilities as a treatment when other measures have failed.