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Unlabelled: The ability to measure tumor determinants of response to nucleoside analog (NA) chemotherapy agents such as gemcitabine and related compounds could significantly affect the management of several types of cancer. Previously we showed that the accumulation in tumors of the new PET tracer 1-(2'-deoxy-2'-(18)F-fluoro-β-d-arabinofuranosyl)cytosine ((18)F-FAC) is predictive of responses to gemcitabine. (18)F-FAC retention in cells requires deoxycytidine kinase (dCK), a rate-limiting enzyme in the deoxyribonucleoside salvage metabolism and in gemcitabine conversion from an inactive prodrug to a cytotoxic compound. The objectives of the current study were to determine whether (18)F-FAC tumor uptake is also influenced by cytidine deaminase (CDA), a determinant of resistance to gemcitabine; to develop a new PET assay using (18)F-FAC and the related probe 1-(2'-deoxy-2'-(18)F-fluoro-β-l-arabinofuranosyl)-5-methylcytosine (l-(18)F-FMAC) to profile tumor lesions for both dCK and CDA enzymatic activities; and to determine whether this PET assay can identify the most effective NA chemotherapy against tumors with differential expression of dCK and CDA., Methods: Isogenic murine leukemic cell lines with defined dCK and CDA activities were generated by retroviral transduction. A cell viability assay was used to determine the sensitivity of the isogenic cell lines to the dCK-dependent NA prodrugs gemcitabine and clofarabine. In vitro enzymatic and cell-based tracer uptake assays and in vivo PET with (18)F-FAC and l-(18)F-FMAC were used to predict tumor responses to gemcitabine and clofarabine., Results: dCK and CDA activities measured by kinase and tracer uptake assays correlated with the sensitivity of isogenic cell lines to gemcitabine and clofarabine. Coexpression of CDA decreased the sensitivity of dCK-positive cells to gemcitabine treatment in vitro by 15-fold but did not affect responses to clofarabine. Coexpression of CDA decreased (18)F-FAC but not l-(18)F-FMAC, phosphorylation, and uptake by dCK-positive cells. (18)F-FAC and l-(18)F-FMAC PET estimates of the enzymatic activities of dCK and CDA in tumor implants in mice were predictive of responses to gemcitabine and clofarabine treatment in vivo., Conclusion: These findings support the utility of PET-based phenotyping of tumor nucleoside metabolism for guiding the selection of NA prodrugs.

A wide variety of chemotherapeutic agents including 1-beta-D-arabinofuranosylcytosine can induce cell death by apoptosis. However, an appropriate method for early detection of apoptosis that can be clinically applicable to peripheral blood samples freshly obtained from leukemic patients under chemotherapy has not yet been established. We investigated the chronology of ara-C induced apoptosis in CCRF-CEM cells by monitoring the expression of a number of apoptotic markers in a time- and concentration-dependent manner with the aim of estimating the earliest reliable marker of apoptosis to apply to clinical drug sensitivity assays. We employed the following techniques: 1) Pulsed field gel electrophoresis to detect high molecular weight DNA fragmentation; 2) FACS analysis for evaluation of APO 2.7 expression and phosphatidylserine externalization; 3) May-Grunwald-Giemsa staining for studying gross morphology; and 4) TUNEL assay to detect multitudes of terminal 3'-OH groups of oligonucleosomal DNA fragments. At 10 microM ara-C, high molecular weight DNA fragmentation was observed after 4 hours incubation being the earliest marker to manifest. APO 2.7 expression and phosphatidylserine externalization were detected almost simultaneously at 6 hours, with marked similarity in their kinetics. Emergence of apoptotic bodies then followed after 12 hours incubation and, finally, oligonucleosomal DNA fragments were demonstrated by positive TUNEL assay at 48 hours. The results suggest the time-sequential expression of each individual marker and introduce high molecular weight DNA fragmentation assay as the most suitable candidate for early detection of sensitivity of malignant cells to apoptosis-inducing anticancer agents, including ara-C.

Cytarabine (Cyt) is an antimetabolite used primarily in the treatment of leukemia, and both immediate and delayed hypersensitivity reactions have been reported. We studied a 9-year-old girl with lymphoblastic leukemia, who developed three anaphylactoid reactions during Cyt treatment courses over a 1-year period. Three years later, Cyt was required again. Although a skin test was negative to Cyt at the concentration of 4 micrograms/ml, we decided on placebo-controlled administration of the drug. The Cyt was well tolerated, and urine values of N-methylhistamine showed no important variations throughout this period compared to those during the placebo administration. Skin tests carried out 14 days after the study were positive at the concentration of 4 micrograms/ml. The history of different episodes of allergic reactions to Cyt, the last one being the most severe, indicated the possible participation of an immediate hypersensitivity phenomenon, but because no studies had been carried out initially, we could not establish the presence of IgE antibodies. These results indicate that good tolerance existed after the control administration procedure. The long interval, 3 years, between the allergic episode and our protocol and the appearance of a positive skin test 14 days after the protocol indicated that the subject had lost sensitivity and become resensitized after the controlled administration procedure.

2',2'-difluorodeoxycytidine (known as dFdC, Gemcitabine and LY188011) is a new analog of deoxycytidine which has demonstrated excellent antineoplastic activity against many kinds of solid tumors and leukemic cell lines. We were interested in the comparison of the antineoplastic activity of this new antimetabolite with cytosine arabinoside (ARA-C) against HL-60 myeloid, RPMI-8392 B-lymphoid and Molt-3 T-lymphoid leukemic cell lines. Our in vitro experiments showed that dFdC was a more potent cytostatic drug than ARA-C against all the leukemic lines with IC50 ranging from 3 to 10 nM for dFdC and from 26 to 52 nM for ARA-C for a 48 h exposure. The cytotoxicity of both drugs was evaluated by clonogenic assay and dFdC was found to be 100 times more potent than ARA-C against all the leukemic cell lines for both a 2 h and a 24 h exposure. The recovery of DNA synthesis after drug removal was much slower for dFdC than for ARA-C. However, in contrast to cytostatic and cytotoxicity results ARA-C was a more potent inhibitor of DNA synthesis than dFdC for all the leukemic cell lines for short exposure. Uptake and elimination of the drugs showed that dFdC accumulated to a higher degree in the leukemic cells than ARA-C and that elimination of this difluoro analog was slower than that of ARA-C. These results indicate that dFdC has more potent in vitro antileukemic activity than ARA-C.

We have treated two pediatric patients with refractory ANLL and four with relapsed high-risk ALL with Adriamycin continuous Ara-C i.v. Four out of six patients were able to enter complete remission after first or second course of the treatment. All of them developed severe bone marrow suppression, and various degree of oral mucositis, liver dysfunction and gastrointestinal toxicity, and two patients died from side effects. Recently this combination chemotherapy is becoming a best regimen for the treatment of untreated ANLL. Although our cases are small in number, this combination therapy also seems to be effective for refractory ANLL and relapsed high-risk ALL. It is needless to say that we have to pay more attention when we use this regimen.

17 patients (age 15-58 years) with refractory acute leukaemia (14 AML, 3 ALL) were treated with high dose cytosine arabinoside (AraC) at a dose of 3000 mg/m2, twice daily for 6 d (13 patients with AraC alone, 4 patients with AraC and doxorubicin). 9 patients achieved complete remission (53%) and 2 a partial remission. Although sophisticated isolation and blood banking facilities are required during the pancytopenic period, the toxicity of this treatment was acceptable. Vomiting, headache, somnolence, fever, conjunctivitis and cardiac arrhythmias were found most frequently. The unexpected pulmonary failure in 3 patients was worrisome. The duration of remissions was from 1 to 12 months. Results obtained with high dose AraC are satisfactory and hold promise for the treatment of patients with previously untreated AML.

A series of 46 patients with acute leukaemia were treated with amsacrine (m-AMSA) and cytosine arabinoside (ara-C). Complete remission (CR) was achieved in 15 of 38 (40%) patients with acute myelogenous leukaemia (AML) and 4 of 8 (50%) patients with acute lymphoblastic leukaemia (ALL). The CR rate was significantly higher (P less than 0.05) for the younger, previously treated patients with AML (9/16) than for the older previously untreated ones (6/22), because of higher treatment mortality in the latter group. Myelosuppression was prolonged and profound. Major nonhaematological toxicity affected the gastrointestinal tract (nausea, vomiting, mucositis, bleeding and ileus associated with severe diarrhoea). Many patients also developed reversible hepatic dysfunction and two elderly patients died of cardiac arrhythmia. Further trials of this combination are justified in patients with relapsed or resistant leukaemia, but for older patients dose reduction is recommended.

The pharmacodynamic parameters of 1-beta-D-arabinofuranosylcytosine (ara-C) in patient plasma and its active anabolite 1-beta-D-arabinofuranosylcytosine-5-triphosphate (ara-CTP) in circulating and bone marrow blast cells were studied in 20 pediatric patients with acute leukemia. ara-C (3 g/m2) was administered as a short-term infusion over 3 h every 12 h for a total of eight doses. The peak plasma concentration of ara-C ranged from 0.02 to 5.6 microM after the first dose of ara-C. The area under the concentration-time curve (AUC) of ara-C in plasma ranged from 302 to 20,298 microMh after the first dose of ara-C. The half-life of elimination (t1/2,el) of ara-C from plasma was 2.4 +/- 1.5 h in three patients with acute nonlymphoblastic leukemia (ANLL) and 4.78 +/- 4.1 h in 9 patients with acute lymphoblastic leukemia (ALL). The intracellular peak concentration of ara-CTP in circulating blast cells averaged 432.2 +/- 14.5 microM and 544.3 +/- 330 microM in patients with ANLL and ALL, respectively. The elimination kinetics of ara-CTP was monoexponential with t1/2,el of 3.30 +/- 0.8 h and 6.9 +/- 2.8 h in patients with ANLL and ALL. DNA synthetic capacity (DSC) of the blast cells was inhibited to between 24 and 64% of control after the first dose of ara-C and it declined further to between 1 and 32% after four doses of ara-C. The AUC of ara-CTP in leukemic cells ranged from 1,073 to 14,751 microMh and it was not related to the AUC of ara-C in plasma. The pharmacodynamic parameters of ara-CTP in circulating blast cells were more homogeneous in patients with ANLL than in patients with ALL. Four of six patients (67%) with ANLL and six of 14 patients (43%) with ALL achieved either complete remission or partial remission with high dose ara-C. We conclude that treatment of pediatric patients with leukemia in relapse with high dose ara-C is tolerable and moderately successful. Inhibition of DSC is positively correlated with the probability of having zero nadir peripheral blast cells. In turn there is a trend for a zero nadir peripheral blast cell count to be related to achievement of a response to therapy. This latter result is consistent with the results of larger studies in adults with leukemia.

In a toxicity study to determine the feasibility of treating patients with acute lymphocytic leukemia (ALL) using an intravenous combination of cytosine arabinoside (Ara-C) and methotrexate (MTX), the drugs were given either simultaneously or sequentially every two weeks. Twenty-nine patients were studied, 17 treated simultaneously, 12 treated sequentially. The tolerated doses of Ara-C and MTX were 60 mg/m2 and 90 mg/m2, respectively, for the simultaneous treatment schedule and 90 mg/m2 and 150 mg/m2, respectively, for the sequential treatment schedule. The dose-limiting factor of the drug combination was gastrointestinal toxicity. The observed recurrent vomiting on both schedules rendered the treatment unsuitable for maintenance therapy.

Of 91 acute leukaemia patients treated with m-Amsa, 19 received intermittent doses, 23 received daily doses and 49 underwent courses with combined m-Amsa and cytosine arabinoside (Ara-C). Intermittent doses had minimal therapeutic activity and toxicity. Among the 23 patients given daily doses, complete remission was observed in 5/12 relapses of ALL and in 2/11 relapses of AML. When Ara-C (200 mg/m2 x 5 days) was administered concomitantly with m-Amsa (200 mg/m2 x 5 days or 120 mg/m2 x 7 days), 17 out of 37 patients with advanced relapses of ALL (13/25 children and 4/12 adults) went into complete remission. While high doses of m-Amsa alone were well tolerated, the combined treatment with high doses of both drugs resulted in severe gastro-intestinal toxicity. Cardiac disorders were observed in patients who had previously received high doses of anthracyclins; there were 5 cases of dysrhythmia and 1 case each of sudden death, ECG alterations and heart failure. In view of its indisputable activity, m-Amsa should be used at an earlier stage in the treatment of acute leukaemias.

Sixty-four patients with refractory acute leukemia were treated with high-dose cytosine arabinoside given at a dosage of 3 g/m2 intravenously over two hours every 12 hours for four to 12 doses, repeated at two- to three-week intervals. Complete remissions were observed in 16 patients (25 percent), and the median duration of remission was three months (range, one to 10 months). Remission rates were similar for patients with acute myelogenous and acute lymphocytic leukemia (24 and 27 percent, respectively). Response rates were significantly higher in patients with initial remission durations of more than six months than in those with shorter remissions or those in whom there was no response to front-line therapy (41 and 9 percent; p less than 0.01). Similarly, patients with disease sensitive to conventional cytosine arabinoside had higher response rates than did those with resistant disease (54 and 17 percent; p = 0.03). Serial in vivo measurements of intracellular concentrations of the active metabolite of cytosine arabinoside in peripheral blasts following the initial dose demonstrated considerable individual variation. Favorable intracellular pharmacology of this active metabolite, manifested by its higher intracellular concentrations 12 hours after the first dose, by longer half-lives of active metabolite levels, and by higher values of the measured area under the curve of its accumulation and retention, was associated with higher response rates. Central nervous system toxicity occurred in 24 percent of patients, and pulmonary toxicity occurred in 22 percent; both were dose-limiting and dose-related. Other toxicities included nausea, vomiting, diarrhea, conjunctivitis, photophobia, cytosine arabinoside fever, skin rashes, and hepatic dysfunction. Response rates were similar for schedules utilizing four to six doses at two-week intervals or nine doses at three-week intervals (27 percent versus 25 percent). The schedule of 12 doses had a more rapid antileukemic effect but resulted in significantly higher toxicity and mortality rates during therapy with a similar overall response rate (21 percent). Thus, high-dose cytosine arabinoside is an effective regimen with substantial toxicity in patients with acute leukemia.

Two patients with poor-prognosis leukemia were treated with high-dose cytosine arabinoside (Ara-C), 3 g/m2, for induction. Both patients developed serious jaundice in the second posttreatment week. Clinically, the jaundice was characterized by conjugated hyperbilirubinemia, normal amino transferase levels, significant elevation of alkaline phosphatase, and no evidence of obstruction. Microscopic examination of the liver showed only passive congestion with blood, and no bile lakes or plugs. This was believed to be most consistent with drug-induced intrahepatic cholestasis, possibly as a result of injury to the hepatocyte transport system.

Four patients with non-Hodgkin lymphoma and two with acute lymphocytic leukemia (ages 4 and 4 months to 16 years 6 months) exhibited a unique reaction to intravenously administered cytosine arabinoside (Ara-C) given alone as a part of the previously reported LSA2-L2 treatment protocol. The syndrome was characterized by fever, myalgia, bone pain, and occasionally by chest pain, maculopapular rash, and conjunctivitis. Each of the eleven episodes of this syndrome occurred within 6-12 hours of drug infusion and always abated after cessation of Ara-C. Prior to the reaction, patients had been on therapy for an average of 13.5 months during which they were exposed to 2298-5387 mg/m2 (mean of 3200 mg/m2) of Ara-C. The high incidence of this syndrome (50% of our patients on the LSA2-L2 regimen and 33% of those receiving Ara-C) has not been previously reported. Considering the prolonged exposure to Ara-C and our inability to document infections in the patients or pyrogens contaminating the drug lots, the most likely explanation for this syndrome is a hypersensitivity reaction to Ara-C. Prevention of these symptoms with corticosteroids supports this contention and provides a reasonable alternative to discontinuing Ara-C.

Three groups of children with acute lymphoblastic leukemia (ALL) were treated with intermittent cyclophosphamide, vincristine, cytosine arabinoside, and prednisone (COAP). Group A (no prior relapse) and Group B (prior single-agent relapse) received COAP after 12 months on another chemotherapy regimen. Children in Group C (prior relapse on multiagent regimens) received COAP following A-COAP (asparaginase plus COAP) reinduction. Median disease-free survival after beginning COAP was not reached for Group A, but was only 7 months for Groups B and C. As of November 1976, there were 8 of 15 Group A patients, 1 of 12 Group B patients, and 1 of 28 Group C patients who had remained disease-free from 38 to 60 (median 54.5) months and were off chemotherapy. COAP has activity in childhood ALL. However, effectiveness is markedly diminished in patients with prior bone marrow relapse.

Combination chemotherapy with VM-26 and ara-C was given to 14 children with acute lymphocytic leukemia who had not responded to initial treatment with prednisone, vincristine, daunomycin, and asparaginase. Nine of these patients had also received ara-C. At diagnosis, five children were classified as having standard prognostic features and nine as being at high risk for treatment failure. The drug combination was administered by vein twice a week for four weeks at dosages of 165 mg/m2 for VM-26 and 300 mg/m2 for araC. Nine complete remissions, five in patients with high-risk leukemia, were induced with acceptable toxicity; all 9 subsequently were given continuation therapy with oral mercaptopurine and methotrexate. Four of the 9 patients have relapsed at 2--21 months. All treatment was stopped in 2 patients after 30 months of complete remission. Combinations of VM-26 and ara-C represent an alternative remission induction treatment for patients who fail to attain initial remission with agents of established effectiveness. These agents may especially benefit patients with prognostic features indicating a high risk of treatment failure.

On the basis of previous findings at this institution, VM-26 and Cytosine Arabinoside (ara-C) were used in combination to treat 33 children with refractory acute lymphocytic leukemia (ALL). Chemotherapy was given by vein twice a week for four weeks at dosage of 300 mg/m2 for ara-C and 50, 75, 110, 165, or 200 mg/m2 for VM-26. Ten marrow remissions (nine complete and one partial) were induced, with hypotension (2/33) and bone marrow hypoplasia (20/33) the most significant side effects observed. Therapeutic responses were obtained with each dosage of VM-26 except 75 mg/m2; myelosuppression developed at all dosages, being most prolonged at 200 mg/m2. Ten of the 23 non-responders did not complete their planned courses of therapy. The significance of this information is that combinations of VM-26 and ara-C were effective in patients who were either in late stages of their leukemia or had never achieved an initial remission. All had been previously treated with prednisone, vincristine, daunomycin and L-asparaginase. In addition, seven of the 10 responders had previously received ara-C in other drug combinations. The use of VM-26 and ara-C in combination may be warranted for newly diagnosed patients who are at high risk for treatment failure with first-line drugs.

Combination chemotherapy with an anthracycline, Adriamycin or rubidazone, cytosine arabinoside, vincristine and prednisone resulted in a complete remission rate of 62% in 325 consecutive unselected adults with acute leukemia. The results by morphologic categories were 58% for acute myelogenous leukemia (AML), 70% for acute undifferentiated leukemia (AUL), and 77% for acute lymphoblastic leukemia (ALL). The median survival was 43 weeks. Ten percent of all patients are projected to be alive and in remission at five years. The median remission duration for the whole group was 51 weeks, durations being significantly longer for AML (60 wks) than ALL (30 wks) and AUL (21 wks). Central nervous system involvement was uncommon in AML (4%), but much more common in patients with AUL (37%) and ALL (32%). One in five complete responders with AML is projected to be in their first remission at five years off all chemotherapy. Age, sex, morphology, cytogenetic pattern, temperature of presentation, and presence of a documented preceding hematologic abnormality are found to be significant variables for response and survival.

Ten patients with acute lymphocytic leukaemia (ALL) and four patients with acute undifferentiated leukaemia (AUL) in relapse or refractory to conventional therapy were treated with remission induction therapy consisting of an anthracycline antibiotic and cytosine arabinoside. Twelve patients had previously demonstrated resistance to vincristine-prednisone and nine patients had prior anthracycline therapy. Nine patients achieved complete remission after one course of therapy with a median time to remission of 30 d. Of five nonresponders, three died of sepsis with marrow hypocellularity and no evidence of residual leukaemia. Only two patients had unequivocal evidence for resistance to an anthracycline-cytosine arabinoside regimen. Myelosuppression and infection were the most significant complications of therapy. The data presented indicate that marrow ablative chemotherapy with an anthracycline antibiotic and cytosine arabinoside is an effective regimen for remission induction in adults with ALL and AUL refractory to vincristine-prednisone. The use of these agents in remission consolidation therapy may offer the possibility of providing a reduction in residual resistant cells that are present after successful remission induction therapy with conventional agents.

Discriminant and regression analyses were employed to determine the influence of a large number of clinical and laboratory indices on outcome of treatment in a series of 158 adults presenting with acute leukaemia between 1970 and 1977. Induction therapy had been most commonly cytosine arabinoside plus daunorubicin, vincristine and prednisolone. This induced complete remission in 42% of non-lymphoblastic, and in 58% of lymphoblastic plus undifferentiated leukaemias. Some induction failures who had non-lymphoblastic leukaemia were treated with cytosine arabinoside plus 6-thioguanine, which induced remissions in 46%. Advanced age was the factor most strongly associated with failure either to achieve or to sustain complete remission. Thrombocytopenia, promyelocytic leukaemia, high percentage of marrow blasts, and absence of metaphases in marrow cytogenetic preparations were also associated with poor survival. A number of other factors which appeared to be associated with poor prognosis were found by the analysis to lack significance as independent variables.

Twenty children with acute lymphoblastic leukemia in second (18 patients) or third (two patients) complete remission after bone marrow relapse received allogeneic bone marrow transplants from histocompatible sibling donors. The preparative regimen for marrow transplantation consisted of 12 doses of 3,000 mg/m2 cytosine arabinoside twice daily for six days followed by 1,200 cGy total-body irradiation (six doses of 200 cGy twice daily for three days). The preparative regimen was well tolerated, and all patients showed marrow engraftment promptly. Twelve patients are alive in complete remission 12+ to 79+ months posttransplant; eight patients are over 48 months posttransplant. Six patients died 1 to 9 months posttransplant of nonleukemic causes: (two each of graft-v-host disease, interstitial pneumonitis, and infection). Two patients developed recurrent leukemia at 15 and 30 months posttransplant. Both have died at 19 and 36 months posttransplant. Life table analysis reveals an actuarial survival and event-free survival rate of 58% and a marrow relapse rate of 17%. These results suggest that high-dose cytosine arabinoside and fractionated total-body irradiation is a relatively nontoxic and highly effective preparative regimen for allogeneic bone marrow transplantation for acute lymphoblastic leukemia that deserves further evaluation.

Children with acute lymphocytic leukemia were examined for evidence of intracranial calcifications with roentgenograms of the skull and computerized tomography. Of 39 children in their initial complete remission, ten were found to have subcortical cerebral calcifications. Significant associations were found between the presence of cerebral calcifications and systemic treatment with large cumulative doses of methotrexate.

Twenty-seven adults with refractory or recurrent acute leukaemia were treated with cytosine arabinoside (ara-C) 2 g/m2 infused over 3 h, every 12 h for 6 days, either alone (regimen A) or with vincristine and prednisolone (regimen B). Complete remission was achieved in 9/18 patients (5/12 regimen A, 4/6 regimen B) with acute lymphoblastic leukaemia (ALL), 1/7 patients (1/5 regimen A) with lymphoid blast crisis of chronic myeloid leukaemia (CML.LBC) and 1/2 patients (1/1 regimen B) with acute undifferentiated leukaemia (AUL). A further 5 patients (4 regimen A, 1 regimen B) with ALL, 4 patients (3 regimen A, 1 regimen B) with CML.LBC and 1 patient (regimen A) with AUL showed evidence of significant response. These results confirm the activity of high-dose a-ra-C in acute non-myelogenous leukaemia and suggest that it might be used with benefit to intensify the initial treatment of 'poor-risk' ALL.

Central nervous system toxicity associated with high-dose cytosine arabinoside (Ara-C) therapy (HD Ara-C) is well known. The authors report the case of a severe isolated peripheral polyneuropathy due to HD Ara-C. Electrophysiologic changes and histologic observations were consistent with axonal degeneration and scattered destruction of myelin sheaths. This observation emphasizes the need for careful complete neurologic evaluation for patients receiving HD Ara-C treatment.

Two young children (3 1/2 years and 19 months) developed seizures within 24 hours of receiving intrathecal cytosine arabinoside. Both had previously received intrathecal cytosine and methotrexate as well as cranial irradiation without untoward effect. Possible mechanisms of causation are discussed and caution is stressed for use of intrathecal cytosine arabinoside in young children.

Ten patients with late-stage acute lymphocytic leukemia were treated with L-asparaginase and cytosine arabinoside. Complete remission was achieved in 8 patients including 5 of 5 patients with T-cell leukemia. Major toxicity included anaphylactic reactions in 3 of the 10 patients.

The combination of arabinosyl cytosine and 6-thioguanine has been effective for the treatment of acute leukemia. Three schedules of this combination were studied to determine which was most effective, especially in patients who had prior exposure to either or both of these drugs. Sequential and simultaneous 5-day courses of the combination were ineffective. A regimen consisting of a 5-day course of arabinosyl cytosine followed by a 5-day course of 6-thioguanine and another 5-day course of arabinosyl cytosine produced responses in 36% of 25 patients. Seven of the nine patients who responded were refractory to prior therapy with arabinosyl cytosine and 5 were refractory tp prior therapy with 6-mercaptopurine. However, the median duration of response was only six weeks. Four patients developed central nervous system complications and three of these patients died while in complete remission. Major toxicity from all three regiments was myelosuppression. This regimen was about as effective as most other regimens used as secondary therapy in patients with acute myelogenous leukemia, but its toxicity was too great for routine usage.

Of the many high-dose Ara-C regimens that have been proposed, the one published by Herzig [24] has been applied most widely. Every 12 h patients receive 3 g/m2 Ara-C for 75-90 minutes for a total of 12 doses. Using that regimen, 25% of patients with refractory acute myelogenous leukemia (AML) and 60% of patients in untreated relapse achieve a complete remission (CR). With few exceptions, complete remissions are obtained after one cycle, median remission duration is between 4 and 6 months. Consolidation or maintenance therapy was not usually given. Currently, numerous modifications of that regimen are under investigation: combinations with other cytostatic agents like anthracyclins, m-AMSA, vincristine; the Capizzi-regimen and intermediate dose Ara-C. Preliminary results of those trials are promising but need to be confirmed by other groups. This survey does not comment on Ara-C toxicity and on Ara-C treatment of CNS leukemia, which are both reviewed in two further articles of this issue.

In a multicenter analysis, the effect of low-dose cytosine arabinoside (Ara-C)(10 mg/ m2q 12 h subcutaneously for a minimum of 15 days) has been assessed in 13 patients with acute leukemia (10 myeloid-AML-, 3 lymphocytic-ALL-) and 7 patients with dysmyelopoietic syndromes (DMPS), conditions classified as refractory anemia with an excess of blasts ( RAEB ). Seven patients suffering from acute leukemia and 1 with DMPS in blastic transformation displayed a leukocytosis of more than 10 X 10(9)/1. Three out of 7 DMPS, 1 out of 10 AML achieved a complete remission, 1 out of 3 ALL-patients reached a partial remission twice. Seven patients showed a blast clearing in the bone marrow and peripheral blood, in another 7 instances examination of the bone marrow was not performed after therapy because of early death. The majority of patients were in their late phase of disease and refractory to conventional chemotherapy. Only 5 patients had no pretreatment at first presentation before low-dose Ara-C was initiated. At least for the DMPS-group, this therapeutic approach seems to be of some benefit.

In this paper, we discuss the cytokinetic basis for optimization of cancer therapy in humans. Specifically, we define a quantitative procedure for determination of the therapeutic acceptability of therapy schedule, discuss studies of the therapeutic gain that might result from treatment of acute lymphoid leukemia (ALL) with cytosine arabinoside (Ara-C), and indicate the kinds of cytokinetic information necessary for therapy scheduling. These studies suggest 1) that substantial therapeutic improvements may result from optimal therapy scheduling, 2) that therapy schedules selected at random are not likely to be beneficial, and 3) that consideration of the cytokinetic properties of the dose limiting normal tissues is critical during therapy design. We also discuss experimental studies of the response to Ara-C of the murine KHT sarcoma. These studies illustrate the substantial cytokinetic changes occur during therapy (e.g., a substantial increase in cell cycle traverse rate and almost complete recruitment) and show the importance of obtaining mid-treatment cytokinetic information about normal and malignant tissues.

Parameters for metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) were examined to know whether the prediction of ara-C sensitivity is possible or not using 9 human lymphoblastic cell lines, 3 T cell lines and 6 B cell lines in vitro. Neither the capacity for synthesis, degradation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), generally lower in the T than B cell lines, nor deamination of ara-C, negligible in the B cell lines, could be correlated to the drug sensitivity. On the other hand, significant correlation was obtained between the sensitivity and the plateau level of ara-CTP. We consider that ara-C sensitivity could be predicted by measuring the plateau ara-CTP level before commencement of chemotherapy.

Pericarditis with tamponade developed in a patient treated with high-dose cytarabine for acute lymphocytic leukemia. Evidence suggests that this was a direct complication of his treatment.

28 consecutive patients (age 15-58 years) with refractory acute leukaemia (24 AML, 4 ALL) have been treated with high or intermediate dose cytosine arabinoside (AraC). Twenty patients received AraC at a dose of 3000 mg/m2, twice daily for 6 days (13 patients AraC alone, 7 patients AraC and doxorubicin) and 8 patients received AraC at a dose of 1000 mg/m2, twice daily for 6 days and daunorubicin. 10 of the 20 patients treated with high dose AraC achieved a complete remission (50%) and 2 a partial remission. No patients in the intermediate dose AraC group achieved a remission (p = 0.05). Toxicity of these protocols was acceptable. Vomiting, headache, somnolence, fever, conjunctivitis, and minor cardiac arrhythmias were found most frequently. The pancytopenic period ranged from 16-30 days for the high dose protocol and 14-23 days for the intermediate dose protocol. Sophisticated isolation and blood banking facilities are required in this period. Median duration of remission was 6 months. Results obtained are in favour of the high dose protocol in refractory leukaemia. Only a large dosage increment of AraC can overcome refractoriness of leukaemic blast cells.

A patient with acute lymphoblastic leukemia refractory to conventional combination chemotherapy schedules was treated with high-dose 1-beta-D-arabinofuranosylcytosine (ara-C) (8 doses of 3 g/m2). The patient achieved complete remission but relapsed 6 weeks later. Two cell lines, PER-145 and PER-163, were established from bone marrow samples obtained before and after treatment, respectively. Both cells represent common acute lymphoblastic leukemia cells (CALLA+, HLA-DR+, sIg-, cIg-). Exposure of the two cell lines to ara-C in vitro revealed that the primary line PER-145 is susceptible to ara-C, while cell line PER-163 is more than 1000-fold more resistant (based on 50% inhibitory doses for growth in culture). Moreover, it was observed that ara-C concentrations from 1 to 33 micrograms/ml resulted in the stimulation of this cell line. Five weeks after his relapse the patient was given another high-dose ara-C course during which the blasts increased by a factor of 10, thus showing a response in vivo similar to that of the PER-163 cells in vitro. This pair of human acute lymphoblastic leukemia cells provides a unique opportunity to investigate the mechanisms underlying the acquired resistance and proliferative response to ara-C.