Clinical experiences with magnetic drug targeting: a phase I study with 4'-epidoxorubicin in 14 patients with advanced solid tumors.

Anticancer drugs reversibly bound to magnetic fluids (ferrofluids) could be concentrated in locally advanced tumors by magnetic fields that are arranged at the tumor surface outside of the organism. If certain requirements are met, systemic toxicity might be minimized, and local tumor efficacy might be increased. We have conducted a Phase I clinical trial using this approach in patients with advanced and unsuccessfully pretreated cancers or sarcomas. Nine such patients received two treatment courses, 3 patients received one course, and 2 patients received three courses of magnetic drug targeting consisting of the infusion of epirubicin in increasing doses (from 5 to 100 mg/m2) that had been chemically bound to a magnetic fluid and the application of magnetic fields to the tumors for 60-120 min. In 2 of 14 patients, the same dose of epirubicin not bound to a magnetic fluid was administered systemically 3 weeks after drug targeting for intraindividual comparisons. Magnetic drug targeting with epirubicin was well tolerated. In one case, a planned second treatment was withdrawn, because of an episode of chills 130 min after infusion of the magnetic drug. Two patients received a third treatment because of good responses after the first two therapies. Based on magnetic resonance tomographic techniques, pharmacokinetics, and the histological detection of magnetites, it was shown that the ferrofluid could be successfully directed to the tumors in about one-half of the patients. Organ toxicity did not increase with the treatment, but epirubicin-associated toxicity appeared at doses greater than 50 mg/m2. Although treatment with magnetic drug targeting seems safe, improvements are necessary to make it more effective and independent of patient- or disease-related problems. A study design to compare conventional treatments with the new treatment form within one patient seems crucial to eliminate interindividual differences.

Preclinical experiences with magnetic drug targeting: tolerance and efficacy.

Although site-specific direction of drugs within an organism would benefit patients with many diseases, active drug targeting is clinically not yet possible. To overcome some of the problems associated with active drug targeting, we have developed a magnetic fluid to which drugs, cytokines, and other molecules can be chemically bound to enable those agents to be directed within an organism by high-energy magnetic fields. In the first part of this study, various concentrations of the magnetic fluid were tested in rats and immunosuppressed nude mice with regard to subjective and objective tolerance. In the second part, the same parameters were evaluated after administration of the ferrofluid to which epirubicin (4'-epidoxorubicin) was chemically bound. Finally, two forms of therapy with the magnetic fluid were tested: tumor treatment by mechanical occlusion with the ferrofluid in high concentrations; and magnetic drug targeting, using small amounts of the ferrofluid as a vehicle to concentrate epirubicin locally in tumors. As a result, the ferrofluid did not cause major laboratory abnormalities; there was no LD50. With very high concentrations of the ferrofluid, animals showed lethargy for 1-2 days. There were no intolerances with the epirubicin-bound ferrofluid as well. Both forms of treatment led to complete tumor responses in an experimental human kidney as well as in a xenotransplanted colon carcinoma model. Thus, the magnetic fluid is a safe agent, which can be used in different ways for local forms of cancer treatment in conjunction with high-energy magnetic fields.

Venules and arterioles in xenotransplanted human colon adenocarcinoma critically constrict with hyperthermia and serotonin.

Local and regional hyperthermia for treatment of cancer is often combined with radio- and chemotherapy. In this study we tested whether topically applied serotonin (5-HT) modulates tumor blood flow during local hyperthermia. The surgically unprepared ear microcirculation of anesthetized (75 mg/kg pentobarbital sodium) female nude athymic (nu/nu) mice (18-25 g) was used. Between 5 and 10 days after passaged pieces of human colon adenocarcinoma cells (1 microliter) had been implanted under the dorsal epidermis of the ear, that ear (tumor diameter 1.5 mm) was fixed on a temperature-regulated stage for measurement (via closed-circuit videomicroscopy) of the diameters of large and small (A1-3) arterioles and venules (V1-4), and capillaries, during local hyperthermia (28 degrees C-45 degrees C) and during local hyperthermia plus 1 mmol/l 5-HT. In the hyperthermia-alone group all skin vessels dilated, whereas all tumor vessels constricted with increasing temperatures. Hyperthermia combined with 5-HT caused dilation of skin arterioles, but skin venules constricted. In contrast, we observed constriction of all microvessels in human tumor xenografts with the combination of hyperthermia and 5-HT. We conclude that hyperthermia and 5-HT, applied intratumorally, could be clinically effective, since normal skin microcirculation is best protected with this treatment, while tumor blood flow is widely reduced.

Growth, microvessel density and tumor cell invasion of human colon adenocarcinoma under repeated treatment with hyperthermia and serotonin.

The intratumoral microvessel density of malignant breast cancer has been shown to be an important prognostic marker. In this study, we tested whether repeated treatment with hyperthermia and serotonin (5-hydroxytryptamine) reduces tumor growth and alters tumor histology of a colon adenocarcinoma, and whether capillary density in this tumor can also be regarded as an important prognostic marker. Previously we have shown that acute treatment of colon adenocarcinoma with hyperthermia, alone or in combination with serotonin, selectively constricted tumor microvessels, which could reduce blood flow and inhibit tumor growth. Fourteen days after human colon adenocarcinoma had been transplanted under the dorsal epidermis of the ear of athymic nude mice, the surgically unprepared tumor-bearing ear of the sodium-pentobarbital-anesthetized animal was treated with hyperthermia alone (group 1, 43 degrees C for 45 min), or with hyperthermia plus topically applied serotonin (1 mM/l, 43 degrees C for 45 min, group 2) twice per week for 5 weeks. Control animals were not treated (group 3). Histological slides (stained with hematoxylin/eosin) were prepared 42 days after implantation, for analysis of tumor grading, tumor cell invasion into the surrounding tissue and microvessels, and the number of intratumoral microvessels. Repeated hyperthermia inhibited tumor growth, reduced the number of intratumoral microvessels, did not change tumor cell invasion and increased the necrotic area. Hyperthermia and serotonin did not influence tumor growth, but strongly reduced cell invasion and the number of microvessels. The area of necrosis was very large. Thus, analysis of microvessel density in colon adenocarcinoma seems not to be an important tool for predicting therapeutic efficacy.

Microvessel diameters of human colon adenocarcinoma during acute treatment with serotonin.

Modulation of tumor blood flow could be of clinical importance, especially when it is combined with radio- or chemotherapy. Serotonin (5-HT), a naturally occurring agent, selectively reduces tumor blood flow and consecutively inhibits the growth of many animal tumors. Therefore, we introduce a new preparation that allows the study of topically applied 5-HT (10(-8) to 10(-2) mol/l) in the microcirculation of a human colon adenocarcinoma. This tumor has been xenotransplanted subcutaneously under the dorsal surface of the ear in athymic nude mice. 5-HT was also tested in the normal skin. The microvascular diameters of large and small arterioles (A1-3) and venules (V1-4) as well as capillaries were measured via closed-circuit videomicroscopy. Normal skin arterioles and venules constricted at higher doses (> 10(-7) mol/l) of 5-HT. In human colon carcinoma, doses of 5-HT higher than 10(-7) mol/l caused constriction of these microvessels; yet, tumor arterioles constricted more than skin arterioles. Thus, 5-HT could selectively reduce blood flow of human colon adenocarcinoma. Based on these findings, we suggest that 5-HT can inhibit growth of human tumors by selectively constricting tumor arterioles.