Activity Of Chemotherapeutic Drugs Research Articles

Is survival improving in stage IV non-small cell lung cancer?

6577 Background: Non small cell lung cancer (NSCLC) represents the number one cause of cancer mortality in the United States. Over several decades clinical research has focused on the development of new, more active chemotherapeutic drugs to improve survival. Over the time period from 1994 to 2003 six drugs have been approved for the treatment of metastatic NSCLC. We are presenting a population based analysis of the survival in patients with metastatic NSCLC in the US from 1981–1990, 1991–1997 and 1998–2003. We also provide a pharmaco-economic view of this observation. Methods: We analyzed the SEER (Surveillance, Epidemiology, and End Results) program database for cancer specific survival rates in stage IV NSCLC patients who were diagnosed between 1980 and 2003 in the SEER catchment geographic areas. The primary exposure of interest was the year of diagnosis. Results: We identified 52,086 eligible patients in total. 8,950, 21,111 and 18,712 patients were diagnosed 1981 to1990, 1991 to 1997 and 1998 to 2003 respectively. The cox proportional hazard ratios were 0.97 (95% CI 0.94–0.99) and 0.85 (0.83–0.88) for the time periods 1991 to 1997 and 1998 to 2003, respectively, using the time period from 1981 to1990 as reference. This subtle increase in survival was strictly paralleled by increasing costs for the medical care of this patient population. Conclusions: The survival of stage IV NSCLC patients seems to be mildly improving, what is paralleled by increasing cost for the care of those patients. [Table: see text] No significant financial relationships to disclose.

Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells.

The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD-321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3 or M-Panc96 cells, which were sensitized to gemcitabine 6.2- and 4.6-fold, respectively. In the more sensitized cells lines, PD-321852 not only inhibited gemcitabine-induced Rad51 focus formation and the recovery from gemcitabine-induced replication stress, as evidenced by persistence of gamma-H2AX, but also depleted these cells of Rad51 protein. Our data suggest the inhibition of this Chk1-mediated Rad51 response to gemcitabine-induced replication stress is an important factor in determining gemcitabine chemosensitization by Chk1 inhibition in pancreatic cancer cells.

Bevacizumab Beyond Progression: Does This Make Sense?

Bevacizumab Beyond Progression: Does This Make Sense?

Cetuximab plus bevacizumab in patients (pts) with metastatic colorectal cancer (mCRC) who have failed on irinotecan, oxaliplatin and fluoropyrimidines-based chemotherapy

14576 Background: Bevacizumab (AVASTIN®) and Cetuximab (ERBITUX®) are IgG1 monoclonal antibodies targeting the Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR), respectively. Both are active in mCRC pts as first and/or second line treatment. Preclinical data suggest potentially synergistic effect for the combination of the two antibodies. This phase II trial evaluates the safety and efficacy of cetuximab combined with Bevacizumab in the treatment of mCRC pts who have failed on Irinotecan, Oxaliplatin and Fluoropyrimidines-based chemotherapy. Methods: mCRC pts with ECOG PS = 2 who had refractory disease to all three active chemotherapeutic drugs were enrolled. Determination of EGFR status was not mandatory. Cetuximab was given at an initial dose of 400mg/m2, then 250mg/m2 iv weekly; Bevacizumab was administered at a dose of 10 mg/kg on d1 every 2 weeks. Results: From June 2005 to November 2006, 14 pts were enrolled. Median age was 65 years, and median PS was 1. Treatment was 3rd-line in 5 pts, and = 4th-line for 7 patients. 12 pts had received prior treatment with Cetuximab and 6 were Bevacizumab. Thirty-nine cycles were administered with a median of 3 cycles/patient. All pts were evaluable for toxicity and response. No grade 3–4 hematological toxicity was observed. Non-hematological toxicities included grade 3 fatigue (7.1%), grade 2 diarrhea (7.1%), grade 2 allergic reactions (14.1%). Amongst the 14 patients evaluable for response, there was 1 objective PR (7.1%; 95% CI: 6- 24%), and 2 (14.2%) SD (tumor growth control rate, TGCR: 21.3%). The median time to progression was 2.4 months and the median survival has not yet been reached. The estimated probability for 1-year survival was 65.7%. Conclusions: The combination of Cetuximab plus Bevacizumab in patients with mCRC refractory or resistant all active chemotherapeutic drugs is safe and has promising activity. No significant financial relationships to disclose.

Expression of a novel alternatively spliced UCP-2 transcript in osteogenic sarcoma

BackgroundDevelopment of chemoresistance is common in patients with osteogenic sarcoma (OGS); however, the underlying mechanism is largely unknown. Many anticancer drugs exert their therapeutic action by generating reactive oxygen radicals, which might be countered by the cancer cell through induction of uncoupling protein 2 (UCP-2). UCP-2 has been shown to be able to protect tumor cells from the cytotoxic actions of chemotherapeutic drugs. Because OGS is seldom completely cured by current chemotherapy regimens, we hypothesized that increased expression of UCP-2 underlies this phenomenon. The primary initial interest of our research was to evaluate the level of UCP-2 mRNA in OGS. MethodsThe level of UCP-2 mRNA was determined by reverse transcriptase polymerase chain reaction (RT-PCR) comparing expression in normal-bone-derived specimens and OGS-derived specimens. Semiquantification of mRNA expression was achieved by radioactive RT-PCR. Nucleotide sequencing was performed using automated instruments. ResultsInterestingly, we failed to observe induction of UCP- 2 mRNA in OGS tumor specimens and OGS-derived primary cell lines compared to the expression level in normal bone. However, we found expression of a hitherto unknown UCP-2 transcript in eight of eight OGS-derived and one EWSderived cell lines and in nine of ten OGS biopsy specimens but in only one of six normal bone-derived specimens. Thus, tumor samples express both types (normal and the novel one) of UCP-2 mRNAs, whereas normal bone expresses only the wild-type form. Further experiments identified the novel mRNA species as an alternatively spliced UCP-2 transcript (termed UCP-2as). UCP-2as has a 22-nucleotide insertion from the 3′ end of intron 3 that introduces an early stop codon in exon 4, which theoretically can produce a protein 79 amino acids long. ConclusionsWe have identified a hitherto unknown UCP-2 transcript. Expression of the novel transcript appears to be OGS-specific, implying a function advantageous to the tumor.

European Lung Cancer Working Party Clinical Practice Guidelines. Non-Small Cell Lung Cancer: III. Metastatic disease

The present guidelines on the management of advanced non-small cell lung cancer (NS CLC) were formulated by the ELCWP in October 2006. They are designed to answer the following twelve questions: 1) What benefits can be expected from chemotherapy and what are the treatment objectives? 2) What are the active chemotherapeutic drugs for which efficacy has been shown? 3) Which are the most effective platinum-based regimens? 4) Which is the indicated dosage of cisplatin? 5) Can carboplatin be substituted for cisplatin? 6) Which is the optimal number of cycles to be administered? 7) Can non-platinum based regimens be substituted for platinum based chemotherapy as first-line treatment? 8) Is there an indication for sequential chemotherapy? 9) What is the efficacy of salvage chemotherapy and which drugs should be used in that indication? 10) What is the place of targeted therapies? 11) What is the place of chemotherapy in the management of a patient with brain metastases? 12) Which specific drugs can be used for the patient with bone metastases?

Thermodynamic Aspects of Cancer: Possible Role of Negative Entropy in Tumor Growth, its Relation to Kinetic and Genetic Resistance

Chemotherapy can result in partial or temporary remission, but often does not completely eradicate cancer. The treatment failures are, at least in part, due to tumor cell resistance to chemotherapeutics. One contributing factor for impaired responses to chemotherapy is that only proliferating cells are affected by the action of chemotherapeutic drugs (kinetic resistance of tumors). Another contributing factor is the genetic resistance mediated by genes encoding proteins such as ABC transporters. A basic understanding of changes associated with tumorigenesis is needed to design and deploy novel and effective strategies for treating cancers. This paper focuses on aspects of energy flow and entropy in tumorigenesis and changes in the interaction between cancer cells and the host. We propose that correlating those changes with the progression of tumors will assist in the design and deployment of novel and more efficacious strategies for chemotherapy and combined therapies.

Epigenetic changes to the MDR1 locus in response to chemotherapeutic drugs

The mechanism of action of chemotherapeutic drugs and their ability to induce multidrug resistance (MDR) are of relevance to cancer treatment. Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene following chemotherapy can severely limit the efficacy of anticancer agents; however, the manner by which cells acquire high levels of Pgp has not been defined. Herein, we demonstrate that chemotherapeutic drugs induce specific epigenetic modifications at the MDR1 locus, concomitant with MDR1 upregulation mediated by transcriptional activation, and a potential post-transcriptional component. We have established that the mechanisms are not mutually exclusive and are dependent on the methylation state of the MDR1 promoter. MDR1 upregulation did not result in further changes to the CpG methylation profile. However, dramatic changes in the temporal and spatial patterning of histone modifications occurred within the 5' hypomethylated region of MDR1, directly correlating with MDR1 upregulation. Specifically, drug-induced upregulation of MDR1 was associated with increases in H3 acetylation and induction of methylated H3K4 within discrete regions of the MDR1 locus. Our results demonstrate that chemotherapeutic drugs can actively induce epigenetic changes within the MDR1 promoter, and enhance the MDR phenotype.

The role of MAPK pathways in the action of chemotherapeutic drugs.

In this study we have investigated the role of mitogen-induced and stress-activated MAP kinase pathways in the cellular response to taxol, etoposide and ceramide in three different human cancer cell lines: HeLa cervical carcinoma, MCF7 breast cancer and A431 squamous carcinoma cells. The mitogen-induced ERK MAPKs were linked to cell proliferation and survival, whereas the stress-activated MAPKs, p38 and JNK, were connected with apoptosis. Our results show that all drugs activated MAPKs, but that the extent and kinetics of activation were different. In order to assay the biological consequences of drug-induced MAPK activation we employed selective MAPK inhibitors and measured both long-term clonogenic survival as well as short-term parameters including apoptosis, mitochondrial metabolic integrity and cell cycle progression. Our results show that drug induced toxicity is not correlated with any singular parameter, but rather a combination of effects on cell cycle and apoptosis. In certain constellations the modulation of MAPK pathways could enhance or decrease drug efficacies. These effects mainly pertained to the regulation of apoptosis and clonogenic survival, but they were highly dependent on the combination of drug and cell line without any clear patterns of correlations emerging. These results suggest that the modulation of MAPK pathways to enhance the efficacy of chemotherapeutic drugs is of limited value unless it is tailored to the specific combination of drug and cancer.

Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis

The role of chemotherapy for unresectable malignant mesothelioma is unclear. The aims of the present study were to evaluate the methodological quality of published papers relative to chemotherapy or immunotherapy in malignant mesothelioma and to aggregate, for trials having a similar methodology, the response rates in order to identify the most active chemotherapeutic drugs and regimens. The literature relative to this topic, published between 1965 and June 2001 was reviewed. A methodological qualitative evaluation was performed according to the European Lung Cancer Working Party scale, specifically designed for phase II trials. A study was considered as potentially positive if the upper limit of the 95% confidence interval (CI) of the response rate was greater than 20% and positive if the lower limit of the 95% CI was >20%. Eighty-three studies (88 treatment arms) were eligible for the systematic review. Fifty-three arms were considered as positive or potentially positive. No statistically significant difference in the methodological quality was observed between negative and positive studies. Studies were aggregated in four groups according to the presence of cisplatin and/or doxorubicin in the treatment regimen. The combination of cisplatin and doxorubicin had the highest response rate (28.5%; P<0.001). Cisplatin was the most active single-agent regimen. Our systematic qualitative and quantitative overview of the literature suggests that the most active chemotherapeutic regimen, in term of objective response rate, is the combination of cisplatin and doxorubicin and the best single-agent is cisplatin. The combination of these two drugs can be recommended as control arm for future randomised phase III trials.

Inhibitors of MEK1/2 Interact with UCN-01 to Induce Apoptosis and Reduce Colony Formation in Mammary and Prostate Carcinoma Cells

Recent studies have suggested that inhibition of the mitogen activated protein kinase (MAPK) pathway as well as abrogation of cell cycle check-point control can potentiate the lethal actions of chemotherapeutic drugs and radiation. We therefore investigated the impact of combined exposure to the check-point abrogator (UCN-01) in conjunction with MEK1/2 inhibitors upon survival of breast and prostate carcinoma cells. Treatment of cells with UCN-01 alone resulted in prolonged activation of the MAPK pathway. Inhibition of MEK1/2 caused modest reductions in basal MAPK activity and transiently suppressed UCN-01-stimulated MAPK activity below that of MEK1/2 inhibitor alone. Significantly, combined, but not individual, exposure of cells to UCN-01 and MEK1/2 inhibitors enhanced BAX association with mitochondria and triggered release of cytochrome c into the cytosol, accompanied by activation of effector pro-caspases, resulting in a greater than additive potentiation of apoptosis within 18-24h. Radiation exposure of drug treated cells did not further enhance apoptosis. Treatment of cells with both caspase 9 and caspase 8 inhibitors was required to completely inhibit apoptosis in carcinoma cells. Over- expression of Bcl-xL blocked cytochrome c release and cell killing induced by the drug combination. Colony forming assays demonstrated that cells exposed to both agents exhibited a substantial reduction in clonogenic survival compared to either drug alone; moreover, radiation further reduced clonogenic survival despite failing to promote additional apoptosis. Collectively, these data demonstrate that combined exposure of carcinoma cells to UCN-01 and MEK1/2 inhibitors induces apoptosis and interacts with radiation to further reduce clonogenic survival.

P53 Inhibits Adriamycin-Induced Down-Regulation of Cyclin D1 Expression in Human Cancer Cells

The tumor suppressor p53 gene product is an essential component of the cytotoxic pathway triggered by DNA-damaging stimuli such as chemotherapeutic agents and ionizing radiation. We previously demonstrated that adenovirus-mediated wild-type p53 gene transfer could enhance the cytotoxic actions of chemotherapeutic drugs both in vitro and in vivo; however, the molecular mechanism of this chemosensitization is still unclear. Cyclin D1 is a major regulator of the progression of cells into the proliferative stage of the cell cycle. Here we show that infection with an adenovirus vector expressing the wild-type p53 gene (Ad-p53) caused an increase in cyclin D1 protein levels in human colorectal cancer cell lines DLD-1 and SW620; treatment with the anti-cancer drug adriamycin, however, down-regulated their cyclin D1 protein expression in a dose-dependent manner. The suppression of cyclin D1 expression following adriamycin treatment could be blocked by simultaneous Ad-p53 infection. Furthermore, DLD-1 and SW620 cells transfected with the cyclin D1 expression construct displayed increased sensitivity to adriamycin compared to that of the vector-transfected control. Our results suggest that ectopic wild-type p53 gene transfer results in increased cyclin D1 expression and, consequently, sensitizes human colorectal cancer cells to chemotherapeutic agents.

Model to evaluate the toxic effect of drugs: vincristine effect in the mass of organs and in the distribution of radiopharmaceuticals in mice

There are evidences that the biodistribution of radiopharmaceuticals can be modified by some drugs. As chemotherapeutic drugs present important toxic effects, we studied the vincristine effect in the mass of organs and are trying to develop a model to evaluate the action of chemotherapeutic drug using the biodistribution of radiopharmaceuticals. Vincristine was administered ( n=15) into female Balb/c mice, the organs isolated and their mass determined. To study the vincristine effect in the biodistribution of technetium-99m-dimercaptosuccinic acid ( 99 m Tc -DMSA) or technetium-99m-diethylenetriaminepentaacetic acid ( 99 m Tc -DTPA), vincristine (0.03 mg) was administered in the animals ( n=15) in three doses. 99 m Tc -DMSA or 99 m Tc -DTPA was injected 1 h after the last dose. After 0.5 h, the animals were sacrificed and the percentage of radioactivity (%ATI) and the percentage of radioactivity per gram of tissue (%ATI/g) in each organ were calculated. The results have shown that the mass decreased significantly (Wilcoxon test, P<0.05) in thymus, spleen, ovary, uterus, kidneys, pancreas. The %ATI to 99 m Tc -DMSA increased in lung, pancreas, heart, thyroid, brain, and bone, and the %ATI/g increased in uterus, ovary, spleen, thymus, kidney, lung, liver, pancreas, heart, thyroid, brain and bone. To 99 m Tc -DTPA, the %ATI increased in uterus, ovary, spleen, thymus, kidney, lung, liver, stomach, heart and bone, and the %ATI/g increased in uterus, ovary, spleen, thymus, kidney, lung, liver, stomach, heart and bone. The results were statistically significant (Wilcoxon test). The results can be explained by the metabolization, therapeutic, toxicological or immunosupressive action of the vincristine. This model, probably, should be used to evaluate the toxic effect of various drugs.

Apoptosis and cancer chemotherapy.

Apoptosis is a fundamental mechanism of cell death that can be engaged by a range of cellular insults. One of the major modes of action of chemotherapeutic drugs may be via the activation of apoptosis. Understanding how the cell death program is engaged following an insult, and hence why it fails to be engaged in certain settings, offers a novel approach to overcoming the clinical problem of drug resistance. The tumour suppressor gene p53 and its downstream effector genes p21, mdm-2, and gadd45 seem to be important in the cellular response to genotoxic drug induced damage. Considerable evidence has accrued about the effect of mutations of this pathway on drug sensitivity and this is discussed. The expanding Bcl-2 family of proteins also play an important role in the cell death program. Evidence suggests that these proteins may function as integrators of damage signals, and may be the final decision point as to whether a cell lives or dies. These proteins may thus represent a logical target for new approaches to overcoming drug resistance.

Poly(A) Polymerase Specifically Implicated in the Mechanism of Chemotherapeutic Drug Action during Cell Apoptosis

It has recently been established that most anticancer drugs act through the mechanism of apoptosis. It has also been clinically confirmed that drug combinations are more effective than single drugs and various chemotherapeutic strategies have therefore been developed. The experiments described here concern the induction of apoptosis with dimethylsulfoxide (DMSO), a substance with multiple activity especially as an inducer of differentiation, and interferon (IFN), a cytokine well known for its antiviral and antineoplastic effects; they are used alone or in combination. Apoptosis may be regulated at all levels of gene expression including the addition of the poly(A) tail to the 3' end of mRNAs. Poly(A) polymerase (PAP) [EC.2.7.7.19], the enzyme that catalyzes the addition of the poly(A) tail to mRNAs, changes in the process of development, differentiation, transformation and apoptosis. In the present study the induction of HeLa cells to apoptosis (65%) with a DMSO/rIFN-alpha combination resulted in pronounced PAP dephosphorylation and activity reduction. HeLa cells induced to apoptosis (35%) with DMSO gave lower levels of PAP dephosphorylation and reduction of activity and cells induced to apoptosis (18%) with rIFN-alpha gave only limited PAP dephosphorylation and reduction of activity. The implications of these observations for chemotherapeutic drug action at the level of mRNA polyadenylation point to the possible use of PAP as a biological marker for the evaluation of this action.

Hsp27 overexpression inhibits doxorubicin-induced apoptosis in human breast cancer cells.

Previously we demonstrated that heat shock protein 27 (hsp27) overexpression confers resistance to the chemotherapeutic agent doxorubicin in MDA-MB-231 breast cancer cells. Since induction of apoptosis is one underlying mechanism of chemotherapeutic drug action, we investigated the effect of hsp27 overexpression on doxorubicin-induced apoptosis, finding that hsp27 protects MDA-MB-231 cells from apoptosis. We also examined expression of the doxorubicin target, topoisomerase II (topo II), in control and hsp27-overexpressing stable transfectants, as topo II expression is important for both drug sensitivity and the initiation of apoptosis by doxorubicin. The relative levels of both topo IIalpha and beta were higher in the controls than the hsp27-overexpressing clones, suggesting that the apoptotic protective effect of hsp27 overexpression in MDA-MB-231 cells is associated with altered topo II expression.

Human tumor models in the severe combined immune deficient (scid) mouse.

To test a number of established human tumor cell lines and early passage breast cancer (UACC2150) and melanoma cells (UACC1273) for growth in the scid mouse and the tumors' response to conventional chemotherapeutic drugs. Established melanoma (A375, C81-61), colon (SW480), lung (A549), lymphomoblastoid leukemia (LCL-B), promyelocytic leukemia (HL60), prostate (PC-3, DU145), and breast (MCF7) cell lines were injected at subcutaneous (s.c.), intraperitoneal (i.p.), or mammary fat pad (MFP) sites. Tumor volume growth curves and survival curves were established for the various tumor cell lines. Carmustine (BCNU), cisplatin (CDDP), cyclophosphamide (CPA), doxorubicin, dacarbazine (DTIC), tamoxifen and vincristine were injected s.c. or i.p.. The chemotherapeutic drug effects on tumor volumes and survival were determined. Tumor growth occurred with each cell type. After i.p. injection, 90% mortality occurred within 26 to 60 days except for the early passage melanoma cell line UACC1273 with which mortality occurred within approximately 90 days. In the MCF7 breast model, treatment with tamoxifen (P < 0.001) and CPA (P < 0.0001) resulted in significant tumor growth delay compared with control groups. BCNU and CDDP resulted in significant tumor growth delays relative to control in SW480 colon cancer (P < 0.0014) and A375 melanoma (P < 0.0001) models, respectively. CPA and doxorubicin improved survival in the HL60 leukemia model (P = 0.0018). These scid mouse human tumor models appear to reflect the clinical situation in that clinically active chemotherapeutic drugs are similarly active in the scid mouse models. Therefore, the scid mouse models may be useful for testing new chemotherapeutic agents against various human cancer types.

Improved efficacy of chemotherapy by parvovirus-mediated sensitisation of human tumour cells.

Increasing resistance of tumour cells towards the cytotoxic action of chemotherapeutic drugs is a major limitation in the treatment of cancer patients. The non-pathogenic human adeno-associated viruses (AAV) have been reported to sensitise HeLa cervical cancer cells to gamma irradiation in vivo and in vitro. To test whether these parvoviruses might render other human tumour cells more sensitive towards chemotherapeutic drugs, we analysed the effects of AAV type 2 (AAV-2) infection on established cancer cell lines and freshly explanted tumour biopsies treated with chemotherapeutic agents (e.g. cisplatin). AAV-2 infection significantly increased the cytotoxic activity of chemotherapeutic drugs compared with uninfected controls. AAV-2 infection without concomitant chemotherapeutic treatment had no significant effect on viability of the cells. In nude mice, combined application of AAV-2 infection and chemotherapeutic treatment significantly increased the therapeutic activity on tumours arising from subcutaneously injected tumour cells compared with tumours treated by chemotherapeutics only. These results indicate that AAV-2 infection sensitises human cancer cells towards the cytotoxic action of chemotherapeutic drugs.

Clinical, toxicological and pharmacological aspects of gemcitabine

Gemcitabine (2’,2’-difluorodeoxycytidine; dFdCyd) is a novel deoxycytidine analogue with both structural and metabolic similarities to cytarabine. Gemcitabine and cytarabine each differ from the nucleotide deoxycytidine by modifications at the 2’ position of the sugar moiety in the molecule, by having two fluorine atoms or one hydroxyl group in this position, respectively (Figure 1). Both drugs require intracellular phosphorylation to their cytotoxic triphosphates. Despite these important similarities, gemcitabine and cytarabine differ greatly in their anti-tumour activities. Cytarabine is one of the most active chemotherapeutic drugs in leukemia, but its activity in solid tumours is minimal. Gemcitabine, on the other hand, has shown activity in a variety of solid tumours. The results of phase I and II studies of gemcitabine have been reviewed before (I). However, since then, more clinical results have become available. This article reviews the current clinical, toxicological and pharmacological data on gemcitabine.

Recombinant transforming growth factor beta 1 and beta 2 protect mice from acutely lethal doses of 5-fluorouracil and doxorubicin.

Transforming growth factor beta 1 (TGF-beta 1) and TGF-beta 2 can reversibly inhibit the proliferation of hematopoietic progenitor cells in vivo, leading us to hypothesize that such quiescent progenitors might be more resistant to high doses of cell cycle active chemotherapeutic drugs, thereby allowing dose intensification of such agents. Initial studies showed that whereas administration of TGF-beta 1 or TGF-beta 2 did not prevent death in normal mice treated with high doses of 5-fluorouracil (5-FU), those mice that received TGF-beta 2 did exhibit the beginning of a hematologic recovery by day 11 after administration of 5-FU, and were preferentially rescued by a suboptimal number of transplanted bone marrow cells. Subsequently, it was found that the administration of TGF-beta 2 protected recovering progenitor cells from high concentrations of 5-FU in vitro. This protection coincided with the finding that significantly more progenitors for colony-forming unit-culture (CFU-c) and CFU-granulocyte, erythroid, megakaryocyte, macrophage (GEMM) were removed from S-phase by TGF-beta in mice undergoing hematopoietic recovery than in normal mice. Further studies showed that the administration of TGF-beta protected up to 90% of these mice undergoing hematologic recovery from a rechallenge in vivo with high dose 5-FU, while survival in mice not given TGF-beta was < 40%. Pretreatment of mice with TGF-beta 1 or TGF-beta 2 also protected 70-80% of mice from lethal doses of the noncycle active chemotherapeutic drug, doxorubicin hydrochloride (DXR). These results demonstrate that TGF-beta can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the nonhematopoietic toxicity of DXR. This report thus shows that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo.