Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome.

AIM: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. LOCATION: Tundra biome. TIME PERIOD: Data collected between 1964 and 2016. MAJOR TAXA STUDIED: 295 tundra vascular plant species. METHODS: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. RESULTS: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. MAIN CONCLUSIONS: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.

Cytochrome P450- and peroxidase-mediated oxidation of anticancer alkaloid ellipticine dictates its anti-tumor efficiency.

An antineoplastic alkaloid ellipticine is a prodrug, whose pharmacological efficiency is dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation in target tissues. The aim of this review was to summarize our knowledge on the molecular mechanisms of ellipticine action in the cancer cells. The CYP-mediated ellipticine metabolites 9-hydroxy- and 7-hydroxyellipticine and the product of ellipticine oxidation by peroxidases, the ellipticine dimer, are the detoxication metabolites of this compound. In contrast, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, derived from two activation ellipticine metabolites, 13-hydroxyellipticine and 12-hydroxyellipticine, generate two major deoxyguanosine adducts in DNA found in the human breast adenocarcinoma MCF-7 cells, leukemia HL-60 and CCRF-CEM cells, neuroblastoma IMR-32, UKF-NB-3, and UKF-NB-4 cells and glioblastoma U87MG cells in vitro and in rat breast carcinoma in vivo. Formation of these covalent DNA adducts by ellipticine is the predominant mechanism of its cytotoxicity and anti-tumor activity to these cancer cell lines. Ellipticine is also an inducer of CYP1A, 1B1, and 3A4 enzymes in the cancer cells and/or in vivo in rats exposed to this compound, thus modulating its own pharmacological efficiencies. The study forms the basis to further predict the susceptibility of human cancers to ellipticine and suggests that this alkaloid for treatment in combination with CYP and/or peroxidase gene transfer increasing the anticancer potential of this prodrug. It also suggests ellipticine reactive metabolites 13-hydroxyellipticine and 12-hydroxyellipticine to be good candidates for targeting to tumors absent from the CYP and peroxidase activation enzymes.

European beech dieback after premature leaf senescence during the 2018 drought in northern Switzerland.

During the particularly severe hot summer drought in 2018, widespread premature leaf senescence was observed in several broadleaved tree species in Central Europe, particularly in European beech (Fagus sylvatica L.). For beech, it is yet unknown whether the drought evoked a decline towards tree mortality or whether trees can recover in the longer term. In this study, we monitored crown dieback, tree mortality and secondary drought damage symptoms in 963 initially live beech trees that exhibited either premature or normal leaf senescence in 2018 in three regions in northern Switzerland from 2018 to 2021. We related the observed damage to multiple climate- and stand-related parameters. Cumulative tree mortality continuously increased up to 7.2% and 1.3% in 2021 for trees with premature and normal leaf senescence in 2018, respectively. Mean crown dieback in surviving trees peaked at 29.2% in 2020 and 8.1% in 2019 for trees with premature and normal leaf senescence, respectively. Thereafter, trees showed first signs of recovery. Crown damage was more pronounced and recovery was slower for trees that showed premature leaf senescence in 2018, for trees growing on drier sites, and for larger trees. The presence of bleeding cankers peaked at 24.6% in 2019 and 10.7% in 2020 for trees with premature and normal leaf senescence, respectively. The presence of bark beetle holes peaked at 22.8% and 14.8% in 2021 for trees with premature and normal leaf senescence, respectively. Both secondary damage symptoms occurred more frequently in trees that had higher proportions of crown dieback and/or showed premature senescence in 2018. Our findings demonstrate context-specific differences in beech mortality and recovery reflecting the importance of regional and local climate and soil conditions. Adapting management to increase forest resilience is gaining importance, given the expected further beech decline on dry sites in northern Switzerland.

Long-term soil water limitation and previous tree vigor drive local variability of drought-induced crown dieback in Fagus sylvatica.

Ongoing climate warming is increasing evapotranspiration, a process that reduces plant-available water and aggravates the impact of extreme droughts during the growing season. Such an exceptional hot drought occurred in Central Europe in 2018 and caused widespread defoliation in mid-summer in European beech (Fagus sylvatica L.) forests. Here, we recorded crown damage in 2021 in nine mature even-aged beech-dominated stands in northwestern Switzerland along a crown damage severity gradient (low, medium, high) and analyzed tree-ring widths of 21 mature trees per stand. We aimed at identifying predisposing factors responsible for differences in crown damage across and within stands such as tree growth characteristics (average growth rates and year-to-year variability) and site-level variables (mean canopy height, soil properties). We found that stand-level crown damage severity was strongly related to soil water availability, inferred from tree canopy height and plant available soil water storage capacity (AWC). Trees were shorter in drier stands, had higher year-to-year variability in radial growth, and showed higher growth sensitivity to moisture conditions of previous late summer than trees growing on soils with sufficient AWC, indicating that radial growth in these forests is principally limited by soil water availability. Within-stand variation of post-drought crown damage corresponded to growth rate and tree size (diameter at breast height, DBH), i.e., smaller and slower-growing trees that face more competition, were associated with increased crown damage after the 2018 drought. These findings point to tree vigor before the extreme 2018 drought (long-term relative growth rate) as an important driver of damage severity within and across stands. Our results suggest that European beech is less likely to be able to cope with future climate change-induced extreme droughts on shallow soils with limited water retention capacity.

Schistosomula, pre-adults and adults of Schistosoma mansoni ingest fluorescence-labelled albumin in vitro and in vivo: implication for a drug-targeting model.

SUMMARY OBJECTIVE: Bilharziosis is one of the most important helminthal infections in humans and is caused by blood flukes of the genus Schistosoma. Three different life stages of the parasite occur within the mammalian host: schistosomula located in the skin, pre-adults located in the lung and adult worms located in the portal venous system. Erythrocytes are a major source of nutrient supply for adults. However, sources of nutrition for the developing stages are still unclear. METHODS: To investigate whether schistosomula, pre-adults and adults of Schistosoma mansoni ingest human serum albumin (HSA) in vitro, these life stages were incubated with aminofluorescein-labelled human serum albumin (Afl-HSA) for 5 h. To test the uptake of albumin in vivo, the albumin conjugate was given intravenously to S. mansoni infected NMRI mice 24 h before harvesting the 3 life stages. RESULTS: In comparison to the control group schistosomula, pre-adults, and adults showed an accumulation of Afl-HSA within the oesophagus and intestinal caecum in vitro and in vivo. CONCLUSION: Our findings suggest that albumin seems to be a major source of energy supply for the early schistosomal life stages and an additive energy support for adult worms. Since albumin has been used successfully as a drug carrier for chemotherapeutic substances against malignant disorders, further studies will focus on albumin as a carrier for anthelminthics in a drug-targeting model.

Global plant trait relationships extend to the climatic extremes of the tundra biome.

The majority of variation in six traits critical to the growth, survival and reproduction of plant species is thought to be organised along just two dimensions, corresponding to strategies of plant size and resource acquisition. However, it is unknown whether global plant trait relationships extend to climatic extremes, and if these interspecific relationships are confounded by trait variation within species. We test whether trait relationships extend to the cold extremes of life on Earth using the largest database of tundra plant traits yet compiled. We show that tundra plants demonstrate remarkably similar resource economic traits, but not size traits, compared to global distributions, and exhibit the same two dimensions of trait variation. Three quarters of trait variation occurs among species, mirroring global estimates of interspecific trait variation. Plant trait relationships are thus generalizable to the edge of global trait-space, informing prediction of plant community change in a warming world.

Cytofluorometric studies on the action of podophyllotoxin and epipodophyllotoxins (VM-26, VP-16-213) on the cell cycle traverse of human lymphoblasts.

Flow microfluorometric analysis of human lymphoid cells exposed in vitro to cytostatic concentrations of podophyllotoxin (0.01-5 mug/ml for 24 h) shows that a major part of this population (40-60%) has the DNA content of cells in the G2-M part of the cell cycle, and that approximately 60% of these cells are arrested in mitosis. Although a similar pattern of DNA distribution is seen in cultures exposed to cytostatic concentrations of VM-26(0.01 mug/ml) and VP--16-213(0.1 mug/ml), no mitotic cells are seen in these cultures. Exposure to higher concentrations: of VM-26 (0.1 mug/ml) and VP-16-213 (1.0 mug/ml) inhibits cell cycle traverse, and after 24 hr of exposure a major part of the population is arrested with the DNA content of cell in the S part of the cell cycle. Exposure to higher drug concentrations leads to a reduction in the number of cells with the late S-G2DNA content. Whereas the cell cycle block induced by cytostatic concentrations of podophyllotoxin (0.01 mug/ml) is readily reversible by reincubation of cells in drug-free medium, cells blocked by VM-26 and VP-16-213 are unable to resume cell-cycle traverse under similar conditions.

The National Cancer Chemotherapy Program.

The National Cancer Chemotherapy Program was initiated in 1955. It is administered and integrated by the Division of Cancer Treatment at the National Cancer Institute. The program involves the discovery and development of potential new antitumor agents; their screening in preclinical experimental systems for antitumor effect, and, if active, for toxicology; and, for selected agents, preliminary, and more definitive clinical trials. While serendipity and empiricism played a substantial role in the early years of the program, the program has increasingly emphasized and been influenced by advances in tumor biology, drug development, clinical pharmacology, and the science of clinical trials. There has been effective interaction between investigator-initiated research on the one hand and developmental research at preclinical and clinical levels on the other. Over 30 chemotherapeutic agents with substantial clinical antitumor activity have been discovered, and their proper use, often in combination and often integrated with surgery or radiotherapy, has resulted in significant progress in the effective treatment of many forms of cancer.

L-dopa: selective toxicity for melanoma cells in vitro.

In a study of the effect of L-dopa, an intermediate in the biosynthesis of the pigment melanin, on the growth of human and murine melanoma cells a highly selective inhibition of growth was observed for pigmented cell lines (S91A and human melanoma) as compared to the nonpigmented control cells (amelanotic melanoma S91B, mouse fibroblast L929, and Chinese hamster ovary). There was a correlation between toxicity and the extent of incorporation of radioactively labeled L-dopa by each line.

Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo.

EMT-6 murine mammary tumors were made resistant to cis-diamminedichloroplatinum (II) (CDDP), carboplatin, cyclophosphamide (CTX), or thiotepa in vivo by treatment of tumor-bearing animals with the drug during a 6-month period. In spite of high levels of in vivo resistance, no significant resistance was observed when the cells from these tumors were exposed to the drugs in vitro. The pharmacokinetics of CDDP and CTX were altered in animals bearing the respective resistant tumors. The resistance of all tumor lines except for the EMT-6/thiotepa decreased during 3 to 6 months in vivo passage in the absence of drugs. These results indicate that very high levels of resistance to anticancer drugs can develop through mechanisms that are expressed only in vivo.

Biotransformation enzymes in development of renal injury and urothelial cancer caused by aristolochic acid.

Ingestion of aristolochic acid (AA) is associated with the development of AA-nephropathy and Balkan endemic nephropathy, which are characterized by chronic renal failure, tubulointerstitial fibrosis, and urothelial cancer. Understanding which enzymes are involved in AA activation and/or detoxification is important in assessing susceptibility to AA. Xiao et al. demonstrate that hepatic cytochrome P450s in mice detoxicate AA and thereby protect kidney from injury. The relative contribution of enzymes activating AA to induce urothelial cancer in humans remains to be resolved.

Prolonged survival of renal allograft in rats by methotrexate-albumin conjugates as immunosuppressive therapy.

Methothrexate (MTX) causes unwanted adverse events by affecting gastrointestinal and bone marrow cells when used as an immunosuppressant. Our aim was to reduce those side effects by covalent binding of methothrexate to human serum albumin (HSA) targeting rapidly proliferating lymphocytes, which are known to ingest albumin as an energy source. Twenty-one rats received a kidney transplant. Group A (n = 5) received standard immunosupression (free MTX); group B (n = 9), albumin-MTX conjugates; and group C (n = 7) albumin control. The primary endpoint of this animal study was transplant survival, which was evaluated as death due to uremia. The study was terminated on day 100. Placebo-treated rat recipients (group C) rejected their grafts at a median of 8 days, which was prolonged to 17 days in standard immunosuppressed rats (group A), resulting in doubling transplant survival compared to nonimmunosuppressed animals. However, the same dose given as HSA-conjugated MTX prolonged the median survival time to 43 days. (group B). Hence, the administration of conjugated methotrexate appeared to result in a doubling of transplant survival compared with standard immunosuppression. Moreover, two animals receiving MTX-HSA became long-term survivors without additional immunosuppression. Further studies should be performed to evaluate the significance of these findings in larger animals and possibly in clinical studies.

The Role of Adsorbed and Subsurface Carbon Species for the Selective Alkyne Hydrogenation Over a Pd-Black Catalyst: An Operando Study of Bulk and Surface.

The selective hydrogenation of propyne over a Pd-black model catalyst was investigated under operando conditions at 1 bar making use of advanced X-ray diffraction (bulk sensitive) and photo-electron spectroscopy (surface sensitive) techniques. It was found that the population of subsurface species controls the selective catalytic semi-hydrogenation of propyne to propylene due to the formation of surface and near-surface PdCx that inhibits the participation of more reactive bulk hydrogen in the hydrogenation reaction. However, increasing the partial pressure of hydrogen reduces the population of PdCx with the concomitant formation of a ß-PdHx phase up to the surface, which is accompanied by a lattice expansion, allowing the participation of more active bulk hydrogen which is responsible for the unselective total alkyne hydrogenation. Therefore, controlling the surface and subsurface catalyst chemistry is crucial to control the selective alkyne semi-hydrogenation.

Cell proliferation in human melanoma.

The cytokinetics of subcutaneous metastases in five patients with melanoma was studied. Multiple simultaneous biopsies following pulse labeling with tritiated thymidine were performed in one patient. There was relatively uniform labeling and mitotic indices among these. Within the individual tumors, there was some variation in the labeling index with small clusters of tumor cells having significantly higher labeling indices than more sparsely infiltrating tumor cells. Repetitive biopsies following pulse labeling were performed in two patients. The per cent labeled mitosis curves were similar in the two patients. By computer analysis a median G(2) period of 5.3 hr and an S period of 21 hr were obtained. The generation time (T(e)) was highly variable with a median of 3 days. This T(e) was consistent with that calculated from grain count studies in these patients. Two patients received either intermittent or continuous tritiated thymidine over a 10-20 day period. Analysis of the labeling index curve by computer fitting indicated a growth fraction of 20-30%. The growth fraction calculated by other indirect methods was consistent with the computer analysis. The potential tumor doubling time as calculated from the T(e) and growth fraction was much shorter than the actual doubling time indicating that cell loss was approximately 70% of the rate of cell production.

Comparison of adjuvant chemotherapy with methotrexate and fluorouracil with and without cyclophosphamide in breast cancer patients with one to three positive axillary lymph nodes.

BACKGROUND: Alkylating agents administered as single agents or in combination with antimetabolites or anthracyclines delay the appearance of metastases and prolong the survival of breast cancer patients after surgery. PURPOSE: This phase III clinical trial was designed to evaluate the therapeutic efficacy and toxicity of the alkylating agent cyclophosphamide in combination with the antimetabolites methotrexate and fluorouracil adjuvant to breast cancer surgery. METHODS: This study consisted of 255 breast cancer patients (a) with one to three histologically positive axillary lymph nodes and either no detectable primary tumor or operable primary tumors 5 cm or less (T0-T2) (95% of the patients) or (b) with tumors larger than 5 cm (T3) and with negative axillary nodes. Patients were randomly allocated to receive either methotrexate (60 mg/m2) and fluorouracil (600 mg/m2) (MF) intravenously on days 1 and 8 every 28 days for eight cycles or cyclophosphamide (100 mg/m2) orally on days 1-14 plus MF (CMF) every 28 days for the same duration. Median follow-up was 7.8 years, and maximum follow-up was 13 years. RESULTS: There were no statistically significant differences in time to treatment failure or overall survival for patients treated with MF or CMF. At 8 years after completion of treatment, time to treatment failure was 55% (95% confidence interval [CI] = 50%-60%) and 59% (95% CI = 54%-64%) and overall survival was 69% (95% CI = 65%-73%) and 67% (95% CI = 62%-72%) for MF- and CMF-treated patients, respectively. The hazard ratios (MF to CMF) for time to treatment failure and for survival, estimated with a proportional hazards model, were 1.02 (95% CI = 0.69-1.50) and 0.87 (95% CI = 0.56-1.34), respectively. Myelosuppression was significantly greater (P < .0001) in CMF-treated patients during cycles 1-6. Median white blood cell count nadirs were between 4.4 x 10(3)/microL and 3.5 x 10(3)/microL in patients receiving MF and between 3.0 x 10(3)/microL and 2.4 x 10(3)/microL in those receiving CMF. Dose reductions were more frequent in CMF-treated patients, which led to statistically significant differences (P < .0001) in amounts of methotrexate and fluorouracil administered. Primary cancers at other sites occurred in 14 patients (5.5%)--six treated with MF and eight treated with CMF. CONCLUSIONS: Our findings suggest that the addition of cyclophosphamide to adjuvant chemotherapy with MF offers no therapeutic advantage but results in increased myelosuppression. IMPLICATIONS: Future trials will define the possible advantages of antimetabolites in adjuvant therapy. Further information will also become available when results of the ongoing National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant MF to CMF in node-negative breast cancer patients are presented.

Intensive combined modality therapy for limited-stage small-cell lung cancer.

BACKGROUND: Conventional-dose chemotherapy for small-cell lung cancer has resulted in high response rates but rarely in a cure. The addition of thoracic radiotherapy (chemoradiotherapy) has improved survival for patients having limited disease, resulting in a median survival of 14-18 months. Previous trials evaluating high-dose chemotherapy and autologous bone marrow transplantation have demonstrated enhanced complete response rates without documenting overall survival benefit. PURPOSE: The purpose of this phase II trial was to determine the disease-free and overall survival, toxic effects, and relapse patterns in patients with limited small-cell lung cancer who were in partial or complete response to first-line conventional-dose chemotherapy and then received intensive systemic combined modality therapy. METHODS: Adults with stage III small-cell lung cancer who had achieved at least a partial response to conventional-dose induction chemotherapy were treated with high-dose cyclophosphamide, cisplatin, and carmustine combined with autologous bone marrow transplantation. Cumulative doses of the three drugs were 5625, 165, and 480 mg/m2, respectively. After recovery, patients received thoracic radiotherapy (50-60 Gy in 25-30 fractions over 5-6 weeks) and cranial radiotherapy (30 Gy in 15 fractions during 3 weeks). RESULTS: Of 19 patients in the study, six had achieved complete response, eight had a greater than 90% reduction in tumor size, and five had a 50%-90% reduction in tumor size. After high-dose therapy, 15 of the 19 were in complete response. Overall, median time to treatment failure after high-dose therapy was 12 months. Overall survival was 73% (95% confidence interval [CI] = 42%-89%) at 1 year and 53% (95% CI = 22%-77%) at 2 years. Of the 14 patients in or near complete response before high-dose therapy, 10 remain disease free with no further chemotherapy a median of 15 (4-69+) months after therapy. Actuarial 2-year disease-free survival is 57% (95% CI = 20%-82%). One patient died of Candida sepsis. Morbidity was low, and most patients returned to full-time work. With the exception of herpes zoster, there were no complications more than 3 months after high-dose therapy. CONCLUSIONS: The majority of the patients in this study are experiencing prolonged and unmaintained disease-free survival. Our findings suggest that patients in or near complete response before high-dose therapy have the most favorable prognosis. IMPLICATIONS: A randomized comparison between this approach and conventional-dose therapy is planned to define the utility of dose intensification with autologous bone marrow transplantation in the treatment of patients with limited-stage small-cell lung cancer who are in or near complete response.

Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I and pharmacologic study.

Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B.

BACKGROUND: Both total dose and dose intensity of adjuvant chemotherapy are postulated to be important variables in the outcome for patients with operable breast cancer. The Cancer and Leukemia Group B study 8541 examined the effects of adjuvant treatment using conventional-range dose and dose intensity in female patients with stage II (axillary lymph node-positive) breast cancer. METHODS: Within 6 weeks of surgery (radical mastectomy, modified radical mastectomy, or lumpectomy), 1550 patients with unilateral breast cancer were randomly assigned to one of three treatment arms: high-, moderate-, or low-dose intensity. The patients received cyclophosphamide, doxorubicin, and 5-fluorouracil on day 1 of each chemotherapy cycle, with 5-fluorouracil administration repeated on day 8. The high-dose arm had twice the dose intensity and twice the drug dose as the low-dose arm. The moderate-dose arm had two thirds the dose intensity as the high-dose arm but the same total drug dose. Disease-free survival and overall survival were primary end points of the study. RESULTS: At a median follow-up of 9 years, disease-free survival and overall survival for patients on the moderate- and high-dose arms are superior to the corresponding survival measures for patients on the low-dose arm (two-sided P<.0001 and two-sided P = .004, respectively), with no difference in disease-free or overall survival between the moderate- and the high-dose arms. At 5 years, overall survival (average +/- standard error) is 79% +/- 2% for patients on the high-dose arm, 77% +/- 2% for the patients on the moderate-dose arm, and 72% +/- 2% for patients on the low-dose arm; disease-free survival is 66% +/- 2%, 61% +/- 2%, and 56% +/- 2%, respectively. CONCLUSION: Within the conventional dose range for this chemotherapy regimen, a higher dose is associated with better disease-free survival and overall survival.

Oxidation pattern of the anticancer drug ellipticine by hepatic microsomes - similarity between human and rat systems.

Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochrome P450 (CYP). We investigated the ability of CYP enzymes in rat, rabbit and human hepatic microsomes to oxidize ellipticine and evaluated suitable animal models mimicking its oxidation in humans. Ellipticine is oxidized by microsomes of all species to 7-hydroxy-, 9-hydroxy-, 12-hydroxy-, 13-hydroxyellipticine and ellipticine N(2)-oxide. However, only rat microsomes generated the pattern of ellipticine metabolites reproducing that formed by human microsomes. While rabbit microsomes favored the production of ellipticine N(2)-oxide, human and rat microsomes predominantly formed 13-hydroxyellipticine. The species difference in expression and catalytic activities of individual CYPs in livers are the cause of these metabolic differences. Formation of 7-hydroxy- and 9-hydroxyellipticine was attributable to CYP1A in microsomes of all species. However, production of 13-hydroxy-, 12-hydroxyellipticine and ellipticine N(2)-oxide, the metabolites generating DNA adducts, was attributable to the orthologous CYPs only in rats and humans. CYP3A predominantly generates these metabolites in rat and human microsomes, while CYP2C3 activity prevails in microsomes of rabbits. The results underline the suitability of rat species as a model to evaluate human susceptibility to ellipticine.

Curative cancer chemotherapy.

Cancer chemotherapy provides variably effective treatment for the majority of forms of human cancer and curative treatment for some 12 categories of cancer. Curative treatment is defined as the proportion of patients who survive beyond the time after which the risk of treatment failure approaches zero, i.e., the disease-free survival plateau. This progress has resulted from a closely integrated scientific effort, including drug development, pharmacology, preclinical modeling, experimental design with respect to clinical trials, quantitative criteria for response, and a series of clinical trials (initially in children with acute lymphocytic leukemia) in which the importance of complete remission, of dose and schedule, of sequencing chemotherapeutic agents, of pharmacological sanctuaries, and particularly of combination chemotherapy was studied. The principles derived from these studies, particularly those relating to combination chemotherapy, resulted in curative treatment for disseminated Hodgkin's disease, non-Hodgkin's lymphoma, pediatric solid tumors, testicular cancer, and limited small cell lung cancer. Many patients with certain stages of solid tumors, such as breast cancer and osteogenic sarcoma, are at high risk of having disseminated microscopic disease. Experimental studies indicate that treatment which is only partially effective against macroscopic disease is much more effective against microscopic tumors. Therefore chemotherapy is administered immediately following control of the primary tumor in patients at high risk of having disseminated microscopic disease, a treatment known as adjuvant chemotherapy. This program has been highly successful in increasing the cure rate in patients with pediatric solid tumors and in prolonging disease-free survival in patients with premenopausal breast cancer. Given dissemination of the technology, it is estimated that 15,000-30,000 patients per year are potentially curable in the United States. Curability of cancer by chemotherapy generally is inversely related to age, i.e., the above tumors are most common in children and young adults. There are new and promising treatment strategies, such as neoadjuvant chemotherapy and autologous bone marrow transplantation. The revolution in molecular and cellular biology is providing an increase in targets, rationale, and opportunity for more effective and novel chemotherapeutic approaches.