Effects of specific active immunization on tumor recurrence following primary tumor resection in WF rats with 1,2-dimethylhydrazine-induced bowel cancer.

Primary gastrointestinal tumors were induced in male WF rats by 16 weekly sc injections of 1,2-dimethylhydrazine [(DMH) CAS: 540-73-8; 20 mg/kg/wk]. Twenty-four to 28 weeks after the start of DMH injections, all rats were surgically explored and gastrointestinal tumors were resected. Rats with no remaining microscopic disease after operation were immunized with one of four tumor isografts. The first isograft, DMH-W163, is a poorly differentiated mucinous adenocarcinoma explanted from a colon cancer in a DMH-treated animal. It has been shown to possess antigens that cross-react with other DMH-induced bowel adenocarcinoma isografts. The second isograft, DMH-W49, is a carcinosarcoma explanted from a DMH-treated primary colon cancer. It has intermediate antigenic cross-reactivity with other colon adenocarcinoma isografts in the WF model. The third isograft, DMH-W15, is a sarcoma explanted from a DMH-induced colon cancer that does not possess antigens cross-reactive with other DMH-induced colon adenocarcinomas. The fourth isograft, SPK, is a spontaneous (non-DMH-induced) renal cell carcinoma that is immunogenic but should not contain tissue-type-specific antigens cross-reacting with the bowel cancers. Immunized rats received three sc weekly injections of 1 X 10(3) irradiated cells. Concomitant control rats received no immunization after resection of the primary tumor. Within 24 weeks of primary tumor resection, 12 of 16 (75%) rats not immunized had tumor recurrence. Only 8 of 24 (34%) rats immunized with DMH-W163 had tumor recurrence (P less than .025 compared to controls). Fifty percent of animals (10/20) immunized with the carcinosarcoma DMH-W49 had a recurrence. Animals immunized with the non-cross-reacting DMH-W15 sarcoma isograft had a recurrence rate similar to that of controls (16/20, 75%). The rats immunized with SPK were not protected from recurrence. Twelve of 19 (63%) had a recurrence at or near the suture line within 24 weeks following primary tumor resection. These results confirm that adjuvant immunotherapy can decrease the rate of recurrence following primary tumor resection in this model. In addition, immunogens that possessed tissue-type-specific antigens were more effective in preventing tumor recurrence than those that did not.

Circulating immune complex levels in patients with gestational trophoblastic neoplasia.

The clinical course, human chorionic gonadotropin (HCG) levels, and serial circulating immune complex (CIC) levels in 21 patients with gestational trophoblastic neoplasia (GTN) were correlated for the evaluation of the relationship between CIC levels and trophoblastic tumor burden. CIC levels were normal in 18 of 21 patients at the time of presentation, and 2 of 3 patients who presented with elevated CIC levels had significant comorbid disease (toxemia and hepatitis). Nine patients were followed into gonadotropin remission, and all 9 developed an increase in CIC levels at the time of remission. It was concluded that CIC, at least as measured by two antigen-nonspecific techniques, is generally not elevated at initial presentation in the patient with GTN; this lack of an elevation is probably due to marked tumor antigen excess. Thus the in vivo importance of CIC as a "blocker" of host antitumor response at this stage is doubtful. After effective treatment as HCG levels return to normal, the demonstrated elevation in serial levels of CIC may reflect a return of adequate host immune response at a time of minimal tumor burden.

Serial circulating immune complex levels and mitogen responses during progressive tumor growth in WF rats.

Inbred male WF rats were given im injections of one of two antigenically and histologically distinct syngeneic tumor isografts, adenocarcinoma DMH-W 163 or spontaneous renal cell carcinoma SPK. Serum and peripheral blood lymphocytes were harvested from tumor-bearing and normal age-matched controls before and after isograft challenge at weekly intervals. Serial circulating immune complex (CIC) levels were quantitated by polyethylene glycol (PEG) insolubilization. T-cell mitogen responses to phytohemagglutinin (PHA) and concanavalin A (Con A) were followed serially. Tumor growth was measured at least weekly. PEG-CIC values rose early after tumor injection, increased with tumor growth, and declined in some animals just before death. Mitogen response to PHA was significantly decreased in isografted tumor-bearing rats, particularly at later stages of tumor development, compared to normal uninoculated controls. Responses to Con A were variable, and suppression was not always seen in tumor bearers. In animals that did not have progressive tumor growth after isograft injection, PEG-CIC levels did not change and responses to PHA were not suppressed. Patterns of CIC change and responses to PHA were not affected by differences in tumor histology or growth rates. Thus serial CIC levels measured by the PEG assay correlate with tumor growth and precede nonspecific suppression of T-cell mitogenic response in these animal tumor models.

Application of polyethylene glycol turbidity assay to detection of circulating immune complexes in cancer patients.

A rapid, reproducible immune complex screening assay was used to quantitate levels of circulating immune complexes in the sera of normal subjects, patients with documented increases in immune complexes from rheumatoid arthritis, patients with clinically or microbiologically documented infections, and patients with cancer. Although wide variations in individual values within the groups were noted and the concurrent elevation of polyethylene glycol-circulating immune complex levels by infection was documented as expected, significant differences were found in the values in patients with cancer compared with those in normal subjects. The overall clinical application of polyethylene glycol-circulating immune complex screening is discussed and current application of screening of serial sera samples from individual patients for correlation with measurable tumor volume is proposed.

Effect of major small bowel resection on dimethylhydrazine-induced bowel carcinogenesis.

We have investigated the effect of distal small bowel resection on chemically induced tumors of the gastrointestinal tract in Wistar/Furth (W/Fu) rats. Dimethylhydrazine (DMH) (20 mg/kg sc once weekly x 16) was commenced 3 months after rats underwent resection of the distal 30 cm of small bowel (one-third resection) or after sham small bowel resection (controls). Fifty weeks after the start of DMH administration, tumors were found in 15 of 25 animals who underwent small bowel resection compared to 9 of 31 animals in the control group (P less than 0.05). After small bowel resection, 8 of 15 tumors occurred at the site of anastomosis but no anastomotic tumors were seen after sham resection. In addition, tumors were larger and more invasive after small bowel resection. These data indicate that major small bowel resection potentiates DMH induced-intestinal carcinogenesis.

Immunogenicity and cross-protection among B16 melanoma variants with differing proclivities to metastasize.

We report here the lack of any relationship between immunogenicity and the potential to metastasize among four B16 melanoma variants. Groups of C57BL/6J mice were immunized with one of four B16 variant lines (maintained by serial IM passage) that were shown in separate experiments to produce the following incidences of pulmonary metastases four to six weeks after isograft excision: M1, 10%-15%; M2 10%-20%; M3, 75%-80%; and M4, 75%-90%. After immunization, mice were challenged with one of the four variant lines in a crisscross fashion. Two challenge doses for each line were chosen on the basis of earlier experiments showing 100% and 50% challenge tumor take in nonimmunized animals. Despite earlier work published from this laboratory showing that splenocytes harvested from immunized mice could distinguish antigenic differences among the B16 variants, we could find no significant difference in immunogenicity or cross-protection among the lines regardless of their metastatic potential. We conclude that no correlation exists between the antigenic differences shown by in vitro splenocyte-mediated cytotoxicity assays among the B16 variants and in vivo immunogenicity or cross-protection experiments. Futhermore, the relationship (if any) between immunogenicity and the ability to metastasize among these B16 variants is not straightforward.