Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1982 Sep;70(3):558–567. doi: 10.1172/JCI110648

Sensitization to Low Dose 5-Fluorouracil

SUBSEQUENT ENHANCEMENT OF ITS SYSTEMIC ANTITUMOR EFFECT IN THE RAT

Rudolf E Falk 1, Mark Hardy 1, Leonard Makowka 1, Julita Teodorczyk-Injeyan 1, Judith A Falk 1
PMCID: PMC370257  PMID: 7107895

Abstract

This report describes a novel method of immunochemotherapy; the active immunization to the drug 5-fluorouracil (5-FU) with enhanced antitumor activity resulting from its subsequent systemic administration. Two metastasizing carcinomas in the Fischer strain (F344) rat have been used: a chemically induced bladder carcinoma (FBCa) and a spontaneous mammary adenocarcinoma (MACa). Both tumors grow rapidly and result in 100% mortality within 10 wk of implantation. Neither tumor is sensitive to systemic 5-FU alone. Intradermal sensitization to 5-FU before FBCa tumor implantation, followed by 5-FU administered systemically, resulted in significant tumor regression and improvement in survival with eradication of all tumor and cure in 20% of animals. A similar antitumor effect was observed with the MACa. A comparable drug effect was observed when methotrexate sensitization was given before FBCa implantation followed by systemic MTX. Specificity to the sensitizing drug was demonstrated by the lack of effect of sensitization with either 5-FU or MTX unless followed by systemic therapy with the requisite sensitizing agent. Sensitization to 5-FU has also been assessed after FBCa implantation followed by resection of the local tumor. Resection was performed after distant tumor metastases had occurred, and was followed by systemic 5-FU therapy. Whereas tumor resection alone failed to cure any animal, sensitization to 5-FU increased cure rate fourfold over animals receiving systemic 5-FU alone. Antibody to 5-FU in the sera of sensitized animals has been suggested by an immunoenzymatic staining technique and its specificity confirmed in a radioimmunoassay. It is postulated that a combination of the systemic agent and the antibody elicited to it by sensitization produces the significant antitumor effect observed. The antitumor effect observed with this new approach to immunochemotherapy warrants further experimental and clinical study.

Full text

PDF
558

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ANSFIELD F. J., SCHROEDER J. M., CURRERI A. R. Five years clinical experience with 5-fluorouracil. JAMA. 1962 Jul 28;181:295–299. doi: 10.1001/jama.1962.03050300015003. [DOI] [PubMed] [Google Scholar]
  2. Blomgren S. E., Wolberg W. H., Kisken W. A. Effect of fluoropyrimidines on delayed cutaneous hypersensitivity. Cancer Res. 1965 Aug;25(7):977–979. [PubMed] [Google Scholar]
  3. Bross I. D., Rimm A. A., Slack N. H., Ausman R. K., Jones R., Jr Is toxicity really necessary? I. The question. Cancer. 1966 Dec;19(12):1780–1784. doi: 10.1002/1097-0142(196612)19:12<1780::aid-cncr2820191204>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  4. CURRERI A. R., ANSFIELD F. J., McIVER F. A., WAISMAN H. A., HEIDELBERGER C. Clinical studies with 5-fluorouracil. Cancer Res. 1958 May;18(4):478–484. [PubMed] [Google Scholar]
  5. Cadman E., Heimer R., Davis L. Enhanced 5-fluorouracil nucleotide formation after methotrexate administration: explanation for drug synergism. Science. 1979 Sep 14;205(4411):1135–1137. doi: 10.1126/science.472732. [DOI] [PubMed] [Google Scholar]
  6. Cohen S. S., Flaks J. G., Barner H. D., Loeb M. R., Lichtenstein J. THE MODE OF ACTION OF 5-FLUOROURACIL AND ITS DERIVATIVES. Proc Natl Acad Sci U S A. 1958 Oct 15;44(10):1004–1012. doi: 10.1073/pnas.44.10.1004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. DANNEBERG P. B., MONTAG B. J., HEIDELBERGER C. Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in vivo. Cancer Res. 1958 Apr;18(3):329–334. [PubMed] [Google Scholar]
  8. ERLANGER B. F., BEISER S. M. ANTIBODIES SPECIFIC FOR RIBONUCLEOSIDES AND RIBONUCLEOTIDES AND THEIR REACTION WITH DNA. Proc Natl Acad Sci U S A. 1964 Jul;52:68–74. doi: 10.1073/pnas.52.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. FRANEK F., RIHA I., STERZL J. Characteristics of gamma-globulin, lacking antibody properties, in new-born pigs. Nature. 1961 Mar 25;189:1020–1022. doi: 10.1038/1891020a0. [DOI] [PubMed] [Google Scholar]
  10. Fernandes D. J., Bertino J. R. 5-fluorouracil-methotrexate synergy: enhancement of 5-fluorodeoxyridylate binding to thymidylate synthase by dihydropteroylpolyglutamates. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5663–5667. doi: 10.1073/pnas.77.10.5663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gershman H., Powers E., Levine L., Van Vunakis H. Radioimmunoassay of prostaglandins, angiotensin, digoxin, morphine and adenosine-3',5'-cyclic-monophosphate with nitrocellulose membranes. Prostaglandins. 1972 May;1(5):407–423. doi: 10.1016/0090-6980(72)90055-x. [DOI] [PubMed] [Google Scholar]
  12. Glaser M. Augmentation of specific immune response against a syngeneic SV40-induced sarcoma in mice by depletion of suppressor T cells with cyclophosphamide. Cell Immunol. 1979 Dec;48(2):339–345. doi: 10.1016/0008-8749(79)90128-x. [DOI] [PubMed] [Google Scholar]
  13. Goldberg N. H., Romolo J. L., Austin E. H., Drake J., Rosenberg S. A. Anaphylactoid type reactions in two patients receiving high dose intravenous methotrexate. Cancer. 1978 Jan;41(1):52–55. doi: 10.1002/1097-0142(197801)41:1<52::aid-cncr2820410109>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  14. Graham R. C., Jr, Karnovsky M. J. The early stages of absorption of injected horseradish peroxidase in the proximal tubules of mouse kidney: ultrastructural cytochemistry by a new technique. J Histochem Cytochem. 1966 Apr;14(4):291–302. doi: 10.1177/14.4.291. [DOI] [PubMed] [Google Scholar]
  15. HARBERS E., CHAUDHURI N. K., HEIDELBERGER C. Studies on fluorinated pyrimidines. VIII. Further biochemical and metabolic investigations. J Biol Chem. 1959 May;234(5):1255–1262. [PubMed] [Google Scholar]
  16. HARTMANN K. U., HEIDELBERGER C. Studies on fluorinated pyrimidines. XIII. Inhibition of thymidylate synthetase. J Biol Chem. 1961 Nov;236:3006–3013. [PubMed] [Google Scholar]
  17. HEIDELBERGER C., ANSFIELD F. J. EXPERIMENTAL AND CLINICAL USE OF FLUORINATED PYRIMIDINES IN CANCER CHEMOTHERAPY. Cancer Res. 1963 Sep;23:1226–1243. [PubMed] [Google Scholar]
  18. Lee F. H., Hwang K. M. Antibodies as specific carriers for chemotherapeutic agents. Cancer Chemother Pharmacol. 1979;3(1):17–24. doi: 10.1007/BF00254415. [DOI] [PubMed] [Google Scholar]
  19. MERRITT K., JOHNSON A. G. STUDIES ON THE ADJUVANT ACTION OF BACTERIAL ENDOTOXINS ON ANTIBODY FORMATION. V. THE INFLUENCE OF ENDOTOXIN AND 5-FLUORO-2-DEOXYURIDINE ON THE PRIMARY ANTIBODY RESPONSE OF THE BALB MOUSE TO A PURIFIED PROTEIN ANTIGEN. J Immunol. 1963 Aug;91:266–272. [PubMed] [Google Scholar]
  20. MUKHERJEE K. L., HEIDELBERGER C. Studies on fluorinated pyrimidines. IX. The degradation of 5-fluorouracil-6-C14. J Biol Chem. 1960 Feb;235:433–437. [PubMed] [Google Scholar]
  21. Makinodan T., Santos G. W., Quinn R. P. Immunosuppressive drugs. Pharmacol Rev. 1970 Jun;22(2):189–247. [PubMed] [Google Scholar]
  22. Mitchell M. S., DeConti R. C. Immunosuppression by 5-fluorouracil. Cancer. 1970 Oct;26(4):884–889. doi: 10.1002/1097-0142(197010)26:4<884::aid-cncr2820260422>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  23. ROCHLIN D. B., SHINER J., LANGDON E., OTTOMAN R. Use of 5-fluorouracil in disseminated solid neoplasms. Ann Surg. 1962 Jul;156:105–113. doi: 10.1097/00000658-196207000-00020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. SANTOS G. W., OWENS A. H., Jr A COMPARISON OF THE EFFECTS OF SELECTED CYTOTOXIC AGENTS ON ALLOGENEIC SKIN GRAFT SURVIVAL IN RATS. Bull Johns Hopkins Hosp. 1965 May;116:327–340. [PubMed] [Google Scholar]
  25. Schreiber R., Raso V. Radioimmunoassay for the detection and quantitation of 5-fluorodexoyuridine. Cancer Res. 1978 Jul;38(7):1889–1892. [PubMed] [Google Scholar]
  26. Spiegelman S., Sawyer R., Nayak R., Ritzi E., Stolfi R., Martin D. Improving the anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4966–4970. doi: 10.1073/pnas.77.8.4966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Tanenbaum S. W., Beiser S. M. PYRIMIDINE-SPECIFIC ANTIBODIES WHICH REACT WITH DEOXYRIBONUCLEIC ACID (DNA). Proc Natl Acad Sci U S A. 1963 May;49(5):662–668. doi: 10.1073/pnas.49.5.662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Weiss R. B., Bruno S. Hypersensitivity reactions to cancer chemotherapeutic agents. Ann Intern Med. 1981 Jan;94(1):66–72. doi: 10.7326/0003-4819-94-1-66. [DOI] [PubMed] [Google Scholar]
  29. da Costa M., Isacoff W., Rothenberg S. P., Iqbal M. P. Protein-methotrexate-IgG complexes in the serum of patients receiving high-dose antifolate therapy. Cancer. 1980 Aug 1;46(3):471–474. doi: 10.1002/1097-0142(19800801)46:3<471::aid-cncr2820460309>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES