Activity of two phase I drugs N-methylformamide (NSC-3051) and Echinomycin (NSC-526417) against fresh surgical explants of human tumors in the 6-day subrenal capsule (SRC) assay.

The potential clinical activity of the new phase I drugs N-methylformamide (N-MF) and Echinomycin (ECH) was examined while still undergoing clinical toxicology trials by testing against fresh surgical explants of human tumors in the 6-day in vivo SRC Assay. Sixty-nine tumors representing different histologic types including breast, lung, colon, ovarian, and cervical, as well as neoplasms of undiagnosed origin, were screened against N-MF (NSC-3051) and ECH (NSC-526417) simultaneously with five standard chemotherapeutic agents used clinically for treatment of the specific type of cancer. Thus, activity of N-MF and ECH could be compared directly with that of standard agents tested in the same assay. Treatment schedule was QD1-5, and the criterion for drug activity was tumor graft regression greater than 20%. N-MF was active against 15/69 tumors with a response rate of 22%. ECH was also active against 15/69 tumors, yielding the same response rate. Although the response rates for N-MF and ECH were the same, indicating a similar degree of general anti-tumor activity as evaluated by the assay, N-MF showed greatest activity against lung tumors whereas ECH was more active against ovarian tumors. Twenty-six of 69 tumors (38%) were unresponsive to all drugs tested, only one tumor was responsive to both N-MF and ECH and no tumors were responsive to either N-MF or ECH alone. Cytoxan, one of the standard agents tested concurrently with both phase I drugs yielded a response rate of 35%, one and one-half times greater. Cervical and renal cancers and lymphomas were relatively unresponsive to both drugs.

Chemotherapy responsiveness of human tumors as first transplant generation xenografts in the normal mouse: six-day subrenal capsule assay.

Feasibility of utilizing human tumors as first transplant generation xenografts in the normal immunocompetent mouse for determining tumor sensitivity to chemotherapeutic agents was demonstrated by applying subrenal capsule (SRC) assay methodology to fresh surgical explants in a six-day time frame. A total of 37 human breast tumors were tested in assays in which 254 xenografts were implanted into control animals. Fifty (20%) of the controls showed some degree of partial regression in the six-day assay period. Using a mean control growth having a positive change in tumor size as the criterion for evaluability, first transplant generation human breast tumors provided an evaluable assay rate of 86%. A tumor response profile was obtained as a result of testing seven clinically active drugs against 32 previously untreated breast cancers. The pattern of responses obtained indicated that no single agent was active against all tumors, nor were tumors which were responsive to one agent necessarily responsive to another, suggesting the feasibility of predicting individual tumor response to specific chemotherapeutic agents. Had these seven drugs been developmental agents of unknown activity which were being tested for the first time against such a panel of human tumors the result would have not only predicted their clinical activity, but the tumor response rates would have also provided an indication of the relative potential of each drug for the specific treatment of breast cancer.

Growth of human tumor xenografts implanted under the renal capsule of normal immunocompetent mice.

The subrenal capsule technique proved effective in demonstrating that the growth of human tumors in normal, immunocompetent animals for 6 days was quantifiable in ocular micrometer units. Positive growth was demonstrable not only with human tumors that had been established in serial transplantation in athymic nude mouse hosts, but also with primary surgical explants. Growth rates of transplantation-established xenograft systems were similar whether implanted in athymic nude or in normal immunocompetent animals indicating that the 6-day time-frame successfully evades growth inhibitory effects of immunologic origin. Immunosuppression with a single dose of cyclophosphamide did not appear to affect growth rate, but permitted the tumors to grow larger extending the time to reach peak size. Significantly, xenografts of primary surgical explants showed positive growth more frequently in 6 days (82%) in the immunocompetent animal than in 11 days (30%) in the immunodeficient athymic nude mouse.