Improved treatment of medullary thyroid cancer in a nude mouse model by combined radioimmunochemotherapy: doxorubicin potentiates the therapeutic efficacy of radiolabeled antibodies in a radioresistant tumor type.

Whereas in advanced metastatic medullary thyroid cancer (MTC), a variety of chemotherapeutic regimens have achieved only limited success clinically, more recently, radioimmunotherapy (RIT) with 131I-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibodies (MAbs) has shown promising results. The aims of this study were to compare, in an animal model, the therapeutic efficacy of RIT to clinically used "standard" chemotherapeutic regimens and to evaluate whether combination strategies of both modalities may be feasible and may help to improve therapeutic results in this rather radioresistant tumor type. Nude mice, bearing s.c. xenografts of the human MTC cell line, TT, were treated either with the 131I-labeled anti-CEA MAb, F023C5 IgG, or were administered chemotherapeutic regimens that had shown promising results in patients with metastatic MTC (doxorubicin and cisplatinum monotherapy, combinations of both agents, and a 5-fluorouracil/dacarbazine/streptozotocin scheme). Control groups were left untreated or were injected with an irrelevant radiolabeled antibody at equitoxic dose levels. The maximum tolerated dose (MTD) of each agent was determined. Combinations of chemotherapy and RIT were evaluated as well. Toxicity and tumor growth were monitored at weekly intervals. From the chemotherapeutic agents and schemes tested, doxorubicin monotherapy was the most effective; combination therapies did not result in an increased antitumor efficacy, but they did result in more severe toxicity. At equitoxic doses, no significant difference was found between the therapeutic efficacy of doxorubicin and that of RIT. Myelotoxicity was dose limiting with radiolabeled MAbs (MTD, 600 microCi), as well as with chemotherapeutic regimens containing alkylating agents (cisplatinum, dacarbazine, or streptozotocin). At its MTD (200 microg), doxorubicin caused only mild myelotoxicity, and despite signs of cardiac toxicity, gastrointestinal side effects were dose limiting. Accordingly, bone marrow transplantation (BMT) enabled dose intensification with RIT (MTD with BMT, 1100 microCi), which led to further increased antitumor efficacy, whereas BMT was unable to increase the MTD of doxorubicin. Due to the complementarity of toxic side effects but an anticipated synergism of antitumor efficacy, combinations of RIT with doxorubicin were tested. Administrations of 500 microCi of 131I-labeled anti-CEA and, 48 h later, 200 microg of doxorubicin (i.e., 83 and 100% of the respective single-agent MTDs), were the highest doses that did not result in an increased lethality; with bone marrow support, 1000 microCi of 131I-labeled anti-CEA could be combined with 200 microg of doxorubicin (i.e., 90 and 100% of the individual MTDs). Therapeutic results of this combined radioimmunochemotherapy were superior to equitoxic monotherapy with either agent, and indication for synergistic antitumor effects is given. At its respective MTD, radioimmunochemotherapy led to a 36% cure rate if it was given without bone marrow support and to a 85% permanent cure rate if it was given with bone marrow support. The animal model, as presented in this study, seems to be useful for the preclinical testing of therapeutic agents for the systemic treatment of MTC. At equitoxic doses, RIT with radiolabeled anti-CEA antibodies seems to be equally as effective as chemotherapy with doxorubicin. Combination of RIT and doxorubicin chemotherapy seems to have synergistic therapeutic efficacy, which may be due to a radiosensitizing effect of doxorubicin.

Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin.

The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1 microg, maximum tumour uptake (8.9+/-2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3+/-1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with 131I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy.