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Disopyramide kinetics were studied in 30 patients with normal to severely impaired renal function (endogenous creatinine clearance 7.6 to 116.9 ml/min/1.73 m2) after intravenous bolus injection. Serum concentration-time curves were fitted to an open two-compartment model. There was close correlation between renal disopyramide clearance and creatinine clearance (r = 0.922). Disopyramide body clearance or elimination rate constant (kel beta) and creatinine clearance did not correlate as closely (r = 0.756 and 0.644). Volume of distribution at steady state and extrarenal clearance of disopyramide both correlated slightly positively with renal function. Disopyramide body clearance and volume of distribution, but not kel beta, were found to be dose dependent. Disopyramide kinetics in renal impairment were not sufficiently predictable from clinical data of the patient because of great interindividual variation in drug disposition and renal and extrarenal elimination. Dosage regimen must therefore be based on individual response and controlled by the clinical effect and estimates of disopyramide serum concentration.

In vitro lymphocyte stimulation by mitomycin-C-blocked tumor cells has been used to demonstrate tumor-specific antigens in syngeneic murine systems and to follow the evolution of tumor immunity with the tumor-bearing state. Mitomycin-blocked tumor cells stimulated syngeneic lymphocytes from normal mice, from those bearing small tumors (less than 1 cm in diameter) and from tumor-immune mice, sensitized by tumor-cell inoculation and subsequent tumor removal, to undergo increased DNA synthesis as measured by the incorporation of tritiated thymidine. However, lymph-node cells from mice bearing tumors over 1 cm in diameter appeared to be maximally stimulated in vivo and incapable of further stimulation by the same tumor cells in vitro. This was reflected by the progressively increasing background levels of nucleic acid synthesis with the length of tumor-bearing and the size of the tumor. Although lymph-node cells from mice with large tumors did not respond to the same tumor cells in vitro, they did have normal responses to PHA. Within 7-14 days of surgical removal of the tumor, specific lymphocyte responsiveness and background activity returned to previous normal levels, but reinoculation with 10-6 tumor cells resulted in progressive tumor growth and loss of specific in vitro responsiveness when the second tumor had reached the critical size of 1 cm in diameter. Brief exposure of tumor-immune lymph-node cells to a soluble antigen extract of the same tumor resulted in a marked increase in DNA synthetic activity compared to that obtained after exposure to a different tumor extract, muscle extract or medium alone underwent stimulation when cultured with mitomycin-blocked tumor cells. However, normally responsive tumor-immune lymph-node cells, after brief exposure to a soluble antigen extract of the same tumor, initially underwent increased DNA synthesis, but were incapable of further stimulation by mitomycin-blocked tumor cells. Tumor antigen, alone or complexed with antibody, was also demonstrated in the sera of mice bearing large tumors and is thought to be responsible for the refractoriness of lymph-node cells from these mice to further stimulation in vitro. These experiments demonstrate that tumor size and the consequent antigen load to which the tumor-bearing animals is subjected have a profound effect on tumor-specific lymphocyte responsiveness.

We tested the ability of the in vitro clonogenic assay (CLAS) to predict clinical response for patients with solid tumors. Patients had objectively measurable disease and received at least one course of chemotherapy. The correlation between clinical responses and in vitro sensitivity was evaluated retrospectively. Tumor types included melanoma (19), sarcoma (five), hepatoma (one), and carcinoma of the stomach (two), colon (three), lung (one), and breast (one). Five patients received two separate courses of chemotherapy with different drugs or drug regimens. In nine of 11 (82%) instances, tumors were sensitive to a particular drug, and the patient had at least 50% regression of tumor following treatment with the tested drug. Two patients whose tumors were sensitive in vitro had no evidence of clinical response. In 25 of 26 assays, the CLAS accurately predicted tumor resistance, and only one patient had evidence of clinical response (96%). Associations of in vitro results with clinical responses were highly significant. The CLAS can accurately predict the chemosensitivity of a variety of solid tumors.

A monoclonal antibody (CALed) against a human pulmonary squamous cell carcinoma line was cytotoxic to the line but did not react to an autologous B-lymphoblastoid line. Although the antibody was thought to be cancer specific, principally on the basis of this evidence, the antibody actually had the A1 Lewis d (Led) specificity. It reacted with approximately 2% of the random donor T-lymphocytes and with all six lymphocytes from donors who were A1 Led type without reacting to lymphocytes of any other type. The monoclonal antibody reactivity was also absorbed out by A1 Led red blood cells but not by red cells of other types. We conclude that the A1 Led antigen had been synthesized by the pulmonary carcinoma lines but not by the autologous lymphoblastoid line, resulting in disparity for this antigen. Since the combination A1 Led only occurs in 2% of the population, it is difficult to distinguish this type of antibody from tumor-specific antibodies.

Natural killer (NK) cytotoxicity was assessed against K562 targets in 14 melanoma patients who received daily im doses of human leukocyte interferon (IFN) for 42 consecutive days. The most common pattern of NK activity was a decline from pretreatment levels 1 day after initiation of treatment, followed by increasing cytotoxicity with peak activity at day 7 and a subsequent gradual decline to pretreatment levels during the remaining weeks of treatment. This pattern was particularly apparent in patients who received 3 x 10(6) or 9 x 10(6) U IFN/day, while patients who received 1 X 10(6) U IFN/day tended to lack the decline at day 1 and maintained the elevated NK activity past day 7. Changes in NK activity could not be related to changes in absolute lymphocyte counts; to proportions of cells bearing membrane receptors for erythrocyte-antibody-complement, of cells bearing FC gamma receptor; or to clinical response to IFN.