Bayard D. Clarkson

Clinical results of treatment with E. coli L‐asparaginase in adults with leukemia, lymphoma, and solid tumors

E. coli L‐asparaginase (A‐ase) was administered to 163 adults with different forms of leukemia, lymphoma, and solid tumors. Six of 11 patients with acute lymphoblastic leukemia and 4 of 32 patients with acute myeloblastic, myelomonoblastic, or undifferentiated leukemia had complete or good partial remissions. Doses of 10 to 5000 IU/kg/day were used, but there was no clear correlation between dose and therapeutic response, nor with any particular preparation of A‐ase. Some of the others had transient physical and/or hematologic improvement, but remission was not achieved. Nineteen patients with myeloblastic leukemia, 4 with lymphoblastic and 3 with undifferentiated, had no response. Eight patients with acute leukemia (7 lymphoblastic and one myeloblastic), who were already in complete remission induced with other agents, were treated with 1000 IU/kg/day or higher doses of A‐ase for one month or longer. Seven were given no further therapy. The disease relapsed within 2‐5 months in 6 patients, but one is still in remission after 8 months. The eighth patient is still in remission after 3 months but is receiving other chemotherapy. Partial hematologic responses occurred in one patient with untreated chronic granulocytic leukemia, in 4 of 5 patients in a blastic phase of chronic granulocytic leukemia, and in 2 of 3 patients with chronic lymphocytic leukemia, but in none of these patients was the response of substantial clinical benefit. Two patients with disseminated lymphosarcoma or reticulum cell sarcoma had excellent therapeutic responses to A‐ase, and 4 others showed some improvement while 14 had no detectable response. Eight patients with advanced Hodgkins disease showed no response. One patient with malignant melanoma with multiple cutaneous metastases had temporary regression of his metastatic nodules with A‐ase on several occasions, but evaluation of this case was complicated by other chemotherapy. Twenty‐nine other patients with melanoma had no response nor did 45 patients with other types of solid tumors. Some toxic manifestations of A‐ase occurred in almost all patients; these were generally more severe and sometimes were intolerable at higher dosage levels. The toxicity will be discussed in detail in an accompanying report.

Cancer Secretomes and Their Place in Supplementing Other Hallmarks of Cancer

The secretome includes all macromolecules secreted by cells, in particular conditions at defined times, allowing cell-cell communication. Cancer cell secretomes that are altered compared to normal cells have shown significant potential for elucidating cancer biology. Proteins of secretomes are secreted by various secretory pathways and can be studied using different methods. Cancer secretomes seem to play an important role in known hallmarks of cancers such as excessive proliferation, reduced apoptosis, immune invasion, angioneogenesis, alteration in energy metabolism, and development of resistance against anti-cancer therapy [1, 2]. If a significant role of an altered secretome can be identified in cancer cells, using advanced mass spectrometry-based techniques, this may allow researchers to screen and characterize the secretome proteins involved in cancer progression and open up new opportunities to develop new therapies. We aim to elaborate upon recent advances in cancer cell secretome analysis using different proteomics techniques. In this review, we highlight the role of the altered secretome in contributing to already recognized and emerging hallmarks of cancer and we discuss new challenges in the field of secretome analysis.

Consideration of the Cell Cycle in Chemotherapy of Acute Leukemia

There is now convincing evidence that it is possible to regularly cure certain experimental leukemias by using chemotherapeutic schedules specifically designed to exploit known information about the kinetic behavior of the leukemic cells, whereas other treatment schedules employing the same or higher total doses of the same drugs fail to effect any cures [1–9]. Much greater difficulty is encountered in treating spontaneous animal leukemias and human leukemia effectively, and the present paper is concerned with what we believe are the main reasons for these different results. To help focus attention on some of the critical points, two representative studies in patients with acute leukemia will be described for illustrative purposes, and general conclusions drawn from these studies in the context of previous information.

Heterotransplantability of human cell lines derived from leukemia and lymphomas into immunologically tolerant rats

Rats were inoculated intravenously with living J‐111 cells on the day of birth to make them immunologically tolerant to human cell antigens. The subcutaneous transplantability of 17 human cell lines was tested in these rats at age 1‐3 weeks. Eight of the cell lines were derived from Burkitts lymphomas (EB 1, EB 2, EB 3, Kudi, Jijoye, Ogun, Raji, SL‐1) one from reticulum cell sarcoma (SK‐RCS1), 6 from leukemia (SK‐L2 SK‐L4, SK‐L6, SK‐L7, SK‐L9, SK‐L10), one from a normal lymph node (SK‐LN1), and one from infectious mononucleosis (C566). Fourteen of these cell lines, including the 2 lines derived from nonmalignant sources, grew as subcutaneous nodules in some of the recipients. The most frequent and largest nodules were produced by lines EB 2 and EB 3 from Burkitt tumors, lines SK‐L2 and SK‐L4 from acute leukemia, and the 2 lines of nonmalignant origin (SKLN1 and C566). More of the cell lines grew subcutaneously in these immunologically tolerant rats than grew on intravenous injection into newborn rats in a previously reported study.

Computer analysis of tracer kinetic data from a human hematopoietic cell line during different phases of growth

Abstract Experiments carried out on a cell line in three phases of growth were analyzed with the aid of a mathematical model of proliferating cell populations. The model incorporates the concepts of both “resting” cells which resume proliferating with constant probability per hour, and quiescent cells which have permanently left the cell cycle. We found that cell loss was significant (about 1 percent per hour) even in log phase populations. In most experiments, few resting cells were present, even in the plateau phase. The mean generation time (excluding the transit time of cells through the resting state) increased from about 20 hr in log phase to about 90 hr in plateau phase, while the mean duration of the G1 phase increased from six to nearly 50 hr. We have also shown how the model can be used to investigate the sensitivity of the results to error or uncertainty in some of the assumptions and parameter values.

Comparative Results Obtained in the Treatment of Acute Leukemia

The current programs used to treat acute leukemia at Memorial-Sloan Kettering Cancer Center are determined on the basis of morphologic criteria and age. The following report describes the regimens used and the current experience at this Center. Although age may be an important factor in the ultimate response of the patient, the morphologic characteristics of the disease govern the therapeutic approach. In acute lymphoblastic leukemia (ALL), the L-2 protocol is used. In the acute non-lymphoblastic leukemias, myeloblastic, myelomonoblastic and monoblastic (AML), the L-6 protocol is followed. The age division is based on practical lines in that there are both adult and pediatric leukemic groups. However, there are only minor differences in the protocols due mainly to practical rather than real considerations.