Faculty Bibliography

Aside from opportunistic infections, several neoplasms have been identified as part of the spectrum of acquired immunodeficiency syndrome (AIDS) as defined by the Centers for Disease Control. Kaposi's sarcoma (KS) was the first such neoplasm to be recognized within the spectrum of AIDS. Although the classic form of Kaposi's sarcoma had been well recognized prior to the epidemic of AIDS, it was quite distinct from the illness that was seen in its "epidemic" form in young homosexual males. In this setting, Kaposi's sarcoma is an aggressive disease, with extensive involvement of skin and mucous membranes, early dissemination to lymph nodes, impressive development of extreme lymphedema, even in the absence of bulky adenopathy, and rapid spread to visceral organs, including lungs and gastrointestinal tract, among others. Although rapid clinical progression and short median survival have been the rule, a spectrum of disease has been seen such that some patients have survived for many years with disease limited to the skin. Certain clinical and laboratory features, such as presence of unexplained fever, night sweats, weight loss ("B" symptoms), or significant T-4-lymphocytopenia, have been identified as indicators of poor prognosis. Various therapeutic interventions have been employed in epidemic KS, and although partial and complete remissions have occurred, no regimen yet reported has significantly improved the survival of treated patients. High-dose recombinant alpha interferon has produced response rates in approximately 30% of treated patients, although toxicity has been observed in approximately 30% as well. Likewise, vinblastine has produced similar response rates with no evidence of long-term efficacy or "cure." Aside from Kaposi's sarcoma, lymphoma primary to the central nervous system was recognized early in the AIDS epidemic as a criterion for inclusion within AIDS in patients less than sixty years of age. Several years after the initial reports of disease, it became apparent that specific types of systemic lymphoma were also quite extraordinary, and the definition of AIDS was amended in June 1985 to include high-grade B-cell lymphomas in individuals who had positive serology or virology for the human immunodeficiency virus (HIV). The AIDS-related lymphomas are characteristic, both pathologically and clinically. The vast majority of these cases have been high-grade B-lymphoid tumors of either immunoblastic or small-non-cleaved type (also known as "undifferentiated," Burkitt, or Burkitt-like).(ABSTRACT TRUNCATED AT 400 WORDS)

Doxorubicin and the bisdioxopiperazine, ICRF 187, synergistically inhibit proliferation of murine sarcoma S180 cells in vitro. Cell cycle analysis was employed to help discriminate cytokinetic from lethal effects of the drug combination. Twenty-four-hour incubation with either agent produced dose-dependent partial G2M arrest. At high doses, ICRF 187 produced partial G2M arrest, inhibition of cell division, and continued DNA synthesis at a higher ploidy, resulting in a second G2M arrest of an 8n population. The addition of ICRF 187 to doxorubicin resulted in enhancement of cell cycle blockade at G2M. The combination also produced enhanced lethality as measured by reduced colony-forming efficiency of drug-treated S180 cells. Measurement of [14C]doxorubicin accumulation in, and effux from, ICRF 187 pretreated cells failed to reveal an effect of pretreatment with the bisdioxopiperazine on anthracycline disposition by S180 cells, suggesting that the enhanced cytotoxic and cytostatic effects do not result from increased intracellular concentrations of doxorubicin. The positive interaction between the two drugs may represent site-specific enhancement of the anthracycline effect by ICRF 187 at an intracellular target site.

A total of 51 patients (eight previously treated) received PALA added to 5-fluorouracil (5FU) given weekly. After 32 patients, the PALA schedule was changed from every other week to weekly, 24 hours preceding 5FU in accordance with preclinical leads (see text). Both schedules were associated with moderately severe toxic effects related primarily to PALA (skin rash) or to the combined effects of both drugs (diarrhea, vomiting, conjunctivitis, and neurotoxicity). Overall nine partial responses were observed, including three in patients previously treated with 5FU. However, future studies with this combination utilizing the current or other previously published schedules are not warranted in colorectal cancer. Since toxicity is a prominent impediment, the possibility of therapeutic synergy may perhaps be explored at drastically reduced doses of PALA, combined with other modulating measures

In vitro studies in exponentially growing L1210 cells utilizing DNA flow cytometry and cell proliferation measurements indicate enhancement of methotrexate effects by Dipyridamole provided: Methotrexate concentrations exceed those required to shut off maximally de novo pathways of purine and pyrimidine synthesis (i.e. 30 nM for 48 h), and Dipyridamole concentrations exceed 3 microM. In 10% fetal calf serum, this concentration inhibits tritiated thymidine uptake by about 80%. These data should prove helpful in the planning of clinical studies with dipyridamole or other inhibitors of nucleoside transport used to potentiate inhibitors of de novo pathways.