Combination therapy for the treatment of tumors

Abstract

The present invention relates to a combination therapy method for treating gastrin-dependent tumors. The method comprises the immunization of a patient with an anti-gastrin 17 immunogenic composition in combination with the administration of chemotherapeutic agents such as 5-fluorouracil and leucovorin.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 09 / 700,402 (abandoned), to Philip C. Gevas, Stephen Grimes, Stephen L. Karr, Susan A. Watson, and Dov Michaeli, filed on May 14, 1999, entitled “COMBINATION THERAPY FOR THE TREATMENT OF TUMORS”, which claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser. No. 60 / 085,687 to Susan A. Watson and Dov Michaeli, filed on May 15, 1998. The subject matter of each of these applications is incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The invention is related to a tumor therapy for inhibiting growth by neutralizing immunologically the growth stimulating peptide hormones in combination with a chemotherapy apply a 5-fluorouracil derivative and leucovorin.BACKGROUND OF INVENTION[0003]Gastrin is a peptide hormone which occurs in two mature forms, tetratriacontagastrin (G34) and heptadecagastrin (G17), and is synthesized and secr...

AI Technical Summary

Benefits of technology

[0019]The present invention provides a combination therapy for treating tumors comprising immunologically neutralizing peptide hormones and factors which promote tumor cell division in combination with chemotherapy. In particular, the present invention provides a method for treating gastrin-dependent cancers, such as colorectal adenocarcinomas. The method comprises a combination therapy comprising anti-G17 immunization of the patient in need of the therapy, in conjunction with the administration of one or more chemotherapeutic agents. The anti-G17 immunization for treating gastrin-dependent tumors is surprisingly effective in generating anti-G17 antibodies, despite the known myelo-suppressive effects of the chemotherapeutic agents used.

[0021]Furthermore, the use of anti-G17 immunization in combination with standard chemotherapy increases the efficacy of colorectal cancer treatment, since in the combination, lower amounts of chemotherapeutic agents may be required to treat a patient, thereby lowering their toxic effects on normal tissues. In addition, the patient's quality of life may be improved and his survival time prolonged.

Problems solved by technology

Thus, the unregulated release of gastrin leads to the abnormal production and secretion of different molecular forms of the hormone.

Specifically, colon carcinoma cells do not efficiently process progastrin resulting in less conversion of precursor gastrin to the mature peptides and, thus, produce mostly incomplete or aberrant gastrins, (Dickinson 1993 and Rehfeld et al.

Surgery is an effective treatment of the primary disease, but it is ineffectual against residual occult disease, which is frequently present.

However, 5-FU therapy has been shown to be only of marginal benefit to the patient, since 5-FU is highly toxic and the therapy is costly and does not appear, alone or in combination with other cytotoxic drugs, to significantly prolong survival.

In most instances, occult or inoperable colorectal tumors do not respond well to chemotherapy or radiation, and new treatments are needed to supplement present procedures.

However, this combination chemotherapy is not without significant morbidity and causes deleterious side effects including stomatitis, diarrhea and myelosuppression (Mahood et al., 1991; Erlichman et al., 1988; Pietnelli et al., 1989), making quality of life an issue, especially in patients with advanced disease.

However, these antagonists have severe toxic side effects and lack specificity, as they block the action of all potential ligands of the receptor such as G34 and CCK in normal cells.

The main problem with these compounds is their lack of potency, with relatively high concentrations required to displace G17 (Watson et al., 1992a; Watson et al., 1992b).

Thus, if complete inhibition of gastrin binding to the receptor does not occur in the autocrine growth cascade, the gastrin antagonists may be unable to block this mechanism of tumor growth promotion.

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