Showing papers in "Anti-Cancer Drugs in 1995"

Docetaxel (Taxotere): a review of preclinical and clinical experience. Part I: Preclinical experience.

Abstract: Docetaxel is a taxoid which is currently in phase II/III clinical trials in Europe, the US and Japan. It was found to promote tubulin assembly in microtubules and to inhibit their depolymerization. In vitro, the docetaxel concentrations required to reduce murine and human cell survival by 50% ranged from 4 to 35 ng/ml and the cytotoxic effects were greater on proliferating than on non-proliferating cells. It was also found to be cytotoxic on fresh human tumor biopsies. In vivo, the drug was found to be schedule independent. A total of 13/14 murine transplantable tumors were found very sensitive to i.v. docetaxel and complete regressions of advanced stage tumors were obtained. Activity was also observed in 15/16 human tumor xenografts in nude mice at an advanced stage. In combination studies, synergism was observed in vivo with 5-fluorouracil, cyclophosphamide and etoposide. Pharmacokinetic evaluation revealed linear pharmacokinetics in tumor-bearing mice. There was a good tumor retention with a 22 h elimination half-life. Plasma protein binding ranged from 76 to 89%. Preclinical toxicology evaluation of docetaxel included single-dose toxicity in rats, mice and dogs, 5-day toxicity in mice and dogs, intermittent-dose toxicity in rats, dogs and monkeys, genetic and reproductive toxicity, as well as investigation of the irritation and sensitization potential. The principal toxicities were hematopoietic (all species), gastrointestinal (dog, monkey) and neuromotor (mice). Dogs appeared to be the most sensitive species. The clinical entry dose of 5 mg/m2 was based on one-third of the 'toxic dose low' in dogs (15 mg/m2).

Preclinical characteristics of gemcitabine

Abstract: Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a nucleoside analogue of deoxycytidine in which two fluorine atoms have been inserted into the deoxyribofuranosyl ring. Once inside the cell gemcitabine is rapidly phosphorylated by deoxycytidine kinase, the rate-limiting enzyme for the formation of the active metabolites gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP). Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for producing the deoxynucleotides required for DNA synthesis and repair. The subsequent decrease in cellular deoxynucleotides (particularly dCTP) favours gemcitabine triphosphate in its competition with dCTP for incorporation into DNA. Reduction in cellular dCTP is an important self-potentiating mechanism resulting in increased gemcitabine nucleotide incorporation into DNA. Other self-potentiating mechanisms of gemcitabine include increased formation of active gemcitabine di- and triphosphates, and decreased elimination of gemcitabine nucleotides. After gemcitabine nucleotide is incorporated on the end of the elongating DNA strand, one more deoxynucleotide is added, and thereafter the DNA polymerases are unable to proceed. This action, termed "masked chain termination", appears to lock the drug into DNA because proof-reading exonucleases are unable to remove gemcitabine nucleotide from this penultimate position. Incorporation of gemcitabine triphosphate into DNA is strongly correlated with the inhibition of further DNA synthesis. Compared with ara-C, gemcitabine serves as a better transport substrate, is phosphorylated more efficiently, and is eliminated more slowly. These differences, together with self-potentiation, masked chain termination and the inhibition of ribonucleotide reductase, which are not seen with ara-C, may explain why gemcitabine is, and ara-C is not, active in solid tumours. This unique combination of metabolic properties and mechanistic characteristics suggests that gemcitabine is likely to be synergistic with other drugs that damage DNA, and also with other modalities such as radiation.

Development of a propidium iodide fluorescence assay for proliferation and cytotoxicity assays.

Abstract: A propidium iodide fluorescence assay (PIA) was developed to characterize the in vitro growth of human tumor cell lines as well as to test the cytotoxic activity of standard compounds. Propidium iodide (PI) was used as a dye which penetrates only damaged cellular membranes. Intercalation complexes are formed by PI with double-stranded DNA which effect an amplification of the fluorescence. Incubation of the total cell population with PI and subsequent fluorescence detection allowed assessment of the number of non-vital cells (first measurement). After freezing the cells at -20 degrees C for 24 h PI had access to total DNA leading to total cell population counts (second measurement). The number of viable cells was calculated by the difference between these two measurements. In the proliferation and cytotoxicity assays 5 x 10(3) cells per well were plated in 96 multiwells and finally stained with 50 micrograms/ml PI in 25 microliters for 10 min. A correlation between the log of cell number and the log of fluorescence units could be demonstrated over a 2.5-3 log range (r = 0.97). The lower limit of cell detection was 150-500 cells/wells. In cytotoxicity assays eight clinically used cytostatics were tested which effected a clear dose-response relationship (r = 0.93-0.98) and high reproducibility (r = 0.92). In conclusion, this assay is a simple and rapid test system, the main advantages are the absence of any washing steps and the small number of tumor cells necessary for drug testing. The PIA can easily be used for cell number determinations in biological and pharmacological studies.

Consequences of angiogenesis for tumor progression, metastasis and cancer therapy.

Abstract: The growth of solid tumors to a clinically relevant size is dependent upon an adequate blood supply. This is achieved by the process of tumor stroma generation where the formation of new capillaries is a central event. Progressive recruitment of blood vessels to the tumor site and reciprocal support of tumor expansion by the resulting neovasculature are thought to result in a self-perpetuating loop helping to drive the growth of solid tumors. The development of new vasculature also allows an 'evacuation route' for metastatically-competent tumor cells, enabling them to depart from the primary site and colonize initially unaffected organs. Several molecular and cellular mechanisms have been identified by which tumor parenchyma may exert its angiogenic effect on host endothelial cells. As a result of this paracrine influence, tumor-associated endothelial cells acquire an 'immature' phenotype manifested by rapid proliferation, migration, release of proteases and expression of cytokines, endothelial-specific tyrosine kinases (e.g. flk-1, tek and others) as well as numerous other molecular alterations. Consequently a network of structurally and functionally aberrant blood vessels is formed within the tumor mass. There is also evidence that endothelial cells themselves, and likewise other stromal cells, may act reciprocally to alter the behavior of adjacent tumor cells in a paracrine or cell contact mediated fashion. For example, production of interleukin 6(IL-6) by endothelial cells may have a differential effect on human melanoma cells expressing different degrees of aggressiveness. In this manner endothelial derived cytokines could conceivably contribute to tumor progression by suppressing the growth of the less aggressive tumor cells and promoting dominance of their malignant counterparts in 'strategic' perivascular zones. Distinct biological features expressed by tumor-associated vasculature may serve as potential prognostic markers of disease progression as well as novel targets for therapeutic intervention.

Cisplatin-associated neurotoxicity: can it be prevented?

Abstract: Neurotoxicity remains the major dose-limiting toxicity of cisplatin Peripheral sensory neuropathy, the primary type of cisplatin neurotoxicity, has been reported in 30-100% of patients with clinical symptoms typically developing after cumulative cisplatin doses of > or = 300 mg/m2 Several clinical studies have established an important dose-response, dose intensity-response and cumulative total dose-response relationship for cisplatin in the treatment of head and neck, testicular, melanoma, and ovarian cancers In patients with these tumor types, the occurrence of moderate or severe neuropathy presents an important therapeutic dilemma Several types of agents--including micleophilic sulfur thiols, neurotrophic factors, phosphonic acid antibiotics and free oxygen radical scavengers--have been investigated for amelioration of cisplatin-related neurotoxicity Of these, amifostine is likely to be the first neuroprotective agent widely used to enhance the clinical effectiveness of cisplatin Recently reported results from a multicenter phase III trial of women with advance ovarian cancer receiving combination chemotheraphy with cisplatin plus cyclophosphamide showed that amifostine pretreatment was associated with moderate but significant reductions in cisplatin-associated peripheral neuropathy, tinnitus and nephrotoxicity, while achieving equivalent pathological response rates and median survival Preclinical data suggest that several additional agents, especially the neurotropic factors nerve growth factor, insulin-like growth factor-I and neurotrophin-3, merit further investigation Nerve growth factor is the only agent reported to prevent, rather than partially protect, cisplatin-induced neuropathy in an experimental model

Apoptosis in murine tumors treated with chemotherapy agents.

Abstract: There is increasing attention directed to the hypothesis that apoptosis plays a role in the response to cancer treatment including chemotherapy. However, the evidence to support this hypothesis has come almost entirely from experiments conducted in cultured cell systems. To extend this hypothesis to the therapeutic setting it is necessary to address this critical question in tumors treated in vivo. We have therefore evaluated the extent of apoptosis induced in murine tumors treated in vivo with cancer chemotherapy agents. Seven different murine tumors, comprising a mammary adenocarcinoma (MCa-4), an ovarian adenocarcinoma (OCa-1), a lymphoma (LY-TH), three sarcomas (FSA, NFSA and SA-NH) and a squamous cell carcinoma (SSC-7), were examined 8 and 24 h after treatment with cisplatin or cyclophosphamide (CY). Apoptosis was scored by morphometric analysis of histological sections of the tumors. The results showed that MCa-4, OCa-1 and LY-TH had a significant apoptotic response to both cisplatin and CY, and the other tumors had essentially no apoptotic response. In addition, two of these tumors, MCa-4 and OCa-1, underwent apoptosis in response to adriamycin, 5-fluorouracil, Ara-C, etoposide, camptothecin and fludarabine. These observations demonstrate that apoptosis may be a feature of tumor response to chemotherapy in vivo, and illustrate the heterogeneity of apoptotic response amongst different tumor types and to different cytotoxic agents.

Docetaxel (Taxotere), a review of preclinical and clinical experience. Part II: Clinical experience.

Abstract: Docetaxel, a promising inhibitor of microtubule depolymerization has shown significant anti-cancer activity during phase I and early phase II trials. The recommended dosage for phase II trials is 100 mg/m2 every 3 weeks which provides optimal activity with tolerable adverse effects. Docetaxel has sh

Use of corticosteroids in neuro-oncology.

Abstract: Glucocorticosteroids (GC) play an important role in the treatment of neuro-oncologic patients. GC are used for the management of malignant brain tumors, either primary of secondary, neoplastic epidural spinal cord compression (NESC), as adjuvant chemotherapy of some central nervous system tumors and perioperatively in brain surgery. GC are believed to exert their influence on brain tumors mainly by reducing the tumor-associated vasogenic edema, probably by decreasing the increased capillary permeability of the blood-brain barrier (BBB). Experimental as well as clinical studies applying computed tomography, magnetic resonance and PET have supported these theories. However, other mechanisms have been proposed and investigated, such as a reduction of cerebral blood flow and oncolytic effects, the latter being controversial. The effect of GC is best observed in patients with cerebral metastases and gliomas. Studies on the effect of non-steroidal anti-inflammatory drugs (NSAIDs) gave conflicting results. Although some prefer methylprednisolone, dexamethasone is the GC given in the majority of neuro-oncologic patients, at an empirically chosen dosage of 4 mg qid. Dose-effect studies in patients with cerebral metastases as well as in patients suffering from NESC have been performed and lower doses in a twice daily regime may be sufficient. Side-effects may be divided in three groups: those originating from the mineralocorticoid activity, the withdrawal of the drug and the chronic excess GC administration. Steroid myopathy is the most frequent occurring serious side-effect in neuro-oncologic patients. Others include gastrointestinal perforation and hemorrhage, opportunistic infections, steroid diabetes, and skin and facial changes. The most important interaction is that with phenytoin. The influence of dexamethasone on the effects of chemotherapy and radiotherapy is also discussed. New developments in GC treatment include the local administration of dexamethasone.

Misconceptions and controversies regarding the use of opioids in cancer pain.

Abstract: The WHO has created a Cancer Pain Relief Programme and developed guidelines for the treatment of cancer pain. Implementation of the analgesic guidelines, assurance of drug availability (specifically opioids), education of healthcare professionals, and designating cancer pain as a priority for all national cancer control programmes are the major goals. Recent studies of medical students, physicians, nurses and state medical boards demonstrate a significant lack of knowledge with regard to the theoretical and practical understanding of the use of analgesic drugs, particularly opioids, in the management of cancer pain. Communication between physicians and patients about pain symptoms has also been shown to be problematic. Limited availability of opioids, their excessive regulation, and the lack of use of alternatives to systemic analgesics also prevent adequate management. Although analgesic drug therapy is the mainstay of treatment, opioid use remains a controversial issue. Some of the controversies include their role in the management of neuropathic pain, which has been suggested to be 'opioid-resistant', as well as the choice of opioid drug. A third controversy is the route of administration. The impetus for the development of novel routes has come from the goals of maximising analgesia, minimising side effects, and providing convenient dosing schedules for patients who require parenteral administration. Other important controversial issues are the development of tolerance and the relationship of pain management to patient requests for physician-assisted suicide and euthanasia.

Safety profile of gemcitabine.

Abstract: This paper reviews the toxicity profile of gemcitabine in a large group of patients (up to 790) from pivotal phase II studies, in which the drug was given intravenously as a 30 min infusion, in a schedule once a week for 3 weeks followed by a week of rest. The safety profile of gemcitabine is unusually mild for such an active agent in solid tumours. Haematological toxicity is mild and short-lived with modest WHO grades 3 and 4 for haemoglobin (6.4% and 0.9% of patients), leukocytes (8.1% and 0.5%), neutrophils (18.7% and 5.7%) and platelets (6.4% and 0.9%). The incidence of grade 3 and 4 infection associated with this level of myelosuppression was low (0.9% and 0.2%). Transaminase elevations occurred frequently, but they were usually mild, and rarely dose limiting. Mild proteinuria and haematuria were seen but were rarely clinically significant. There was no evidence of cumulative hepatic or renal toxicity. Nausea and vomiting was mild, rarely dose limiting, and generally well controlled with standard antiemetics. Flu-like symptoms were experienced in a small proportion of patients but were of short duration. Where oedema/peripheral oedema was experienced there was no evidence of any association with cardiac, hepatic or renal failure. Hair loss was rare, with WHO grade 3 alopecia reported in 0.5% of patients. There was no grade 4 alopecia. Furthermore, gemcitabine displayed minimal toxicity in elderly patients, and the side-effect profile does not seem to be affected by patient age. The adverse events typically experienced with cytotoxic agents, namely myelosuppression, nausea and vomiting and alopecia, are not seen to such a degree with gemcitabine, and this nonoverlapping toxicity profile suggests that gemcitabine is a promising agent for incorporation into combination chemotherapy regimens.

Transdermal fentanyl therapy: system design, pharmacokinetics and efficacy

Abstract: The transdermal route of drug delivery has been used for the effective administration of therapeutic agents for more than a decade The most important consideration in selecting a drug for transdermal delivery is the potential for improving therapeutic efficacy The development of a transdermal fentanyl system provided an opportunity to add fentanyl to the armamentarium of strong opioids available for the treatment of cancer pain The transdermal route of administration has advantages over both the oral and parenteral routes In addition, patient and caregiver factors allow improved acceptance of and compliance to strong opioids and therefore improved analgesic outcome Four transdermal fentanyl systems are available, providing delivery rates ranging from 25-100 micrograms/h; higher rates can be achieved by multiple system application The system releases fentanyl continuously for 3 days when applied to the skin Concentrations of fentanyl in the blood are measurable within a few hours of system application Fentanyl serum concentrations increase gradually, generally levelling off after 12-24 h and remaining relatively constant for the remainder of the 3-day period Steady state serum concentrations are reached by the second application Clinical trials have established the efficacy and safety of transdermal fentanyl for the treatment of cancer pain Transdermal fentanyl is not licensed for the treatment of acute pain, eg postoperative pain, and should not be prescribed for this purpose

Possible mechanisms in the emergence of tamoxifen-resistant breast cancer.

Abstract: Tamoxifen (TAM), a non-steroidal antiestrogen, is the endocrine treatment of choice for all stages of breast cancer. However, despite a favorable initial response to therapy, most tumors will eventually exhibit TAM resistance resulting in disease recurrence. Several mechanisms of TAM resistance have been proposed, yet a single distinct mechanism has not been identified. We will systematically consider the following steps of the estrogen receptor (ER)-mediated signal transduction pathway to identify possible sites of alteration leading to tamoxifen-resistance: (1) ligand metabolism and availability, (2) loss or mutation of the ER, (3) defects in ER post-translational modification, and (4) alteration of the estrogen response element (ERE). In particular, the ERE will be discussed as a position in the signal transduction pathway with considerable potential, if altered, to confer TAM resistance.

Methotrexate chemosensitivity by ATP luminescence in human leukemia cell lines and in breast cancer primary cultures: comparison of the TCA-100 assay with a clonogenic assay.

Abstract: Chemosensitivity assays are widely used to predict the ability of tumor cell lines to respond to potential or existing cytotoxic drugs. In this study we have compared the cell cloning assay first described by Salmon and Hamburger with a recently developed assay which measures viable cell number by ATP luminescence. Methotrexate (MTX) was chosen as the test agent, since cell lines with varying degrees of sensitivity to this agent were readily available. The results shown good correlation between the two assays, both of which are able to discriminate between the various cell lines used. MTX inhibition of primary breast carcinomas and cell lines shows a steep dose-response curve with a threshold concentration above which increasing dose does not increase sensitivity. In solid tumors, the plateau is usually reached at a level well below 100% inhibition. The ATP luminescence assay allows discrimination of MTX sensitivity between breast carcinomas and has considerable technical advantages over the cloning assay.

Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients

Abstract: Fifty-one patients with histologically confirmed epithelial stage III or IV ovarian cancer were entered into a study in which gemcitabine 800 mg/m2 was given as a 30 min intravenous infusion in a cycle once a week for 3 weeks followed by a week of rest. Patients were aged 58 years (range 23-70 years) with WHO performance status 0-2, and had received up to two different chemotherapy regimens. Thirty-eight patients had received only one prior platinum-containing chemotherapy regimen whereas 9 had received a first-line regimen on more than one occasion. A further 3 patients had received two different regimens. Of 42 patients evaluable for response, 8 (19%; 95% CI: 9%-34%) were partial responders. Seven of the 8 responders were resistant to first-line platinum-based therapy. Median duration of response was 8.1 months (range 4.4-12.5 months). Median progression-free survival was 2.8 months (range 0.2-12.5 months). Haematological toxicity with gemcitabine was modest, with grade 3 leukopenia (11 patients) and grades 3 and 4 thrombocytopenia (6 patients). Grade 3 non-haematological toxicity included nausea/vomiting (6 patients) and elevated AST/ALT (1 patient), while dose-limiting non-haematologic toxicity consisted of flu-like symptoms (2 patients), peripheral oedema (1 patient) and lethargy (1 patient). The activity and modest haematological and non-haematological toxicity seen with gemcitabine suggest that this agent should be further evaluated in the treatment of patients with ovarian cancer and in combination chemotherapy regimens, primarily in combination with platinum.

Combination therapy with 5-fluorouracil and L-canavanine: in vitro and in vivo studies

Abstract: L-Canavanine (CAV) is a potent L-arginine antagonist, produced by legumes such as the jack bean, Canavalia ensiformis. CAV is cytotoxic to MIA PaCa-2 human pancreatic cancer cells. We sought to determine whether CAV's efficacy as an anticancer agent might be increased in combination with 5-fluorouracil (5-FU), a pyrimidine antimetabolite with activity against solid tumors. Using optimal conditions for the expression of CAV's cytotoxicity against MIA PaCa-2 cells, CAV was more cytotoxic to the cells than 5-FU. The combination of both drugs at a fixed molar ratio of 1:1 exhibited synergistic effects in the cells as determined by combination index analysis. The combination of 5-FU:CAV was tested at a ratio of 5:1 and exhibited antagonism at lower effect levels, additivity at 50% effect levels and slight synergism at higher effect levels. A 10:1 combination of both drugs (5-FU:CAV) exhibited antagonistic effects at all levels. When the drugs were combined at a molar ratio of 20:1, increased antagonism was observed. When CAV (1.0 or 2.0 g/kg daily) and/or 5-FU (35 mg/kg daily) was administered to colonic tumor-bearing rats for five consecutive days, the antitumor activity of the drug combination was significantly greater than the combined effects of either drug alone. However, the body weight loss experienced by CAV-treated rats was increased in those rats exposed to a combination of both drugs. These studies using different tumors provide in vitro and in vivo evidence that combination therapy offers a viable means of improving CAV's intrinsic efficacy while decreasing the concentration of 5-FU required to produce the same cytotoxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Symptomatic benefit from gemcitabine and other chemotherapy in advanced non-small cell lung cancer: changes in performance status and tumour-related symptoms.

Abstract: Results from recent trials challenge the traditional view that chemotherapy offers no survival or quality of life benefits over best supportive care. Meta-analyses of recent trials reveal a modest survival benefit for combination chemotherapy over best supportive care, although there is no strong evidence from randomized trials for superiority of combination over single-agent therapy. In chemotherapy trials where data on performance status change were collected, performance status improved in one-third of patients and remained constant in a further third. Fewer studies have measured changes in specific disease-related symptoms, but there are data from studies with gemcitabine which show improvements in a range of symptoms, including cough, haemoptysis, pain, dyspnoea and anorexia. Thus more patients benefit from chemotherapy than may be suggested by objective response. Surveys have shown that patients are more likely to accept intensive chemotherapy for what are perceived by health care professionals as potentially small benefits. Studies have shown evidence of cost savings associated with chemotherapy over best supportive care.

Antitumor effect of liposome-incorporated camptothecin in human malignant xenografts.

Abstract: The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT; NSC 94600) and its derivatives. This drug has been reported to display effective antitumor effects on a variety of human tumor models xenografted in nude mice. However cl

Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone.

Abstract: This study examined the growth inhibitory effects of combining 1,25-dihydroxyvitamin D3 (calcitriol) with retinoic acid or dexamethasone against cultured breast and ovarian carcinoma cells. Retinoic acid (12.5-50 nM) increased the effectiveness of calcitriol (12.5-50 nM) against MCF-7 and NIH:OVCAR3 cells, with synergistic interactions at two of the three ratios tested. Dexamethasone augmented calcitriol effects, with synergism at 0.05 and 0.1 nM dexamethasone in MCF-7 cells and 5 nM in Caov-4 ovarian cells. This study showed favorable interactions for calcitriol-retinoic acid and calcitriol-dexamethasone combinations in breast and ovarian cancer cell lines.

Design of synthetic branched-chain polypeptides as carriers for bioactive molecules.

Abstract: New groups of synthetic biodegradable branched chain polypeptides have been prepared with the general formula poly[Lys-(Xi-DL-Alam)] or poly[Lys-(DL-Alam-Xi)] [AXK], where m approximately 3 and i < 1, and used to elucidate structural and functional properties required for the selection of macromolecular carriers for (i) targeting/delivery of antitumor agents (e.g. daunomycin, methotrexate, boron derivatives), peptide hormones (e.g. GnRH antagonist) or radionuclides for imaging (e.g. 123I, 111In, 51Cr) or therapy (e.g. 153Sm, 131I) or (ii) the construction of synthetic antigens with peptide epitopes of mucin or Herpes Simplex virus glycoprotein D. Principles applicable for a rational carrier design are outlined based on chemical (size, charge, solution conformation) and biological (cytotoxicity, pirogenicity, biodegradation, immunogenicity, immunomodulatory potential, biodistribution) characterization of these biopolymers and their conjugates.

The bcl-2 and p53 oncoproteins can be modulated by bryostatin 1 and dolastatins in human diffuse large cell lymphoma.

Abstract: The effects of dolastatin 10 (Dol10) and dolastatin 15 (Dol15) alone, and after treatment with bryostatin 1 (Bryo1), on human diffuse large cell lymphoma cell line (WSU-DLCL2) were studied. At a concentration of 1.0 ng/ml Dol10 and Dol15 showed significant growth inhibition (p < 0.05). This inhibition was intensified when the cells were pretreated for 24 h with 200 nM Bryo1. Bryo1, Dol10 and Dol15 induced apoptosis which was seen on morphological examination, by flow cytometry and DNA fragmentation on agarose gel electrophoresis. Cells pretreated with Bryo1 and then exposed to Dol10 showed an increase in apoptosis compared with cells that were treated with the Dol10, Dol15 alone. Immunocytochemistry revealed that WSU-DLCL2 cells express the bcl-2 oncoprotein constitutively. bcl-2 expression was decreased when cells were treated with Bryo1, Dol10 or Dol15 and abolished with the Bryo1/Dol10 combination. WSU-DLCL2 cells were negative for p53 protein expression, upon treatment with Bryo1 or Dol10, the expression of p53 was weak and moderate with the Bryo1/Dol10 combination. The inverse correlation between bcl-2 and p53 oncoprotein expression seems to be related to induction of apoptosis in this lymphoma cell line.

Phase II trials of single-agent activity of gemcitabine in patients with advanced non-small cell lung cancer: an overview.

Abstract: A total of 361 patients have been entered into four phase II trials in which gemcitabine was given as a 30 min infusion in a schedule weekly x 3 q4W, at starting doses of 800-1250 mg/m2. Three of these trials produced response rates of 22.5%, 20% and 21.8% (all response rates were independently evaluated by an extramural Oncology Review Board). One small study of 30 evaluable patients produced a disappointing low response rate of 3%, but in this study the mean and median dose delivered was under 700 mg/m2. Gemcitabine was well tolerated with modest levels of traditional cytotoxicities such as myelosuppression, nausea and vomiting, and alopecia. Pooled data from two of the studies show improvement in a number of disease-related symptoms. Objective response rates by prognostic factor were determined: stage IIIa (30.5%), stage IIIb (18.8%), stage IV (19.5%); performance status 0 (31.8%), 1 (16.7%) and 2 (21.7%); female gender (23.5%), male (17.5%); age 70 (21.9%). Gemcitabine can be considered for use as a single agent in patients unable or unwilling to tolerate combination chemotherapy. Dose-response data suggest that a dose of 1000 mg/m2 or more is required for optimal therapeutic effect. The single-agent activity of gemcitabine together with its non-overlapping toxicity and novel mode of action suggest that this agent should also be investigated in combination with other active agents in non-small cell lung cancer.

Guidelines for the clinical use of transdermal fentanyl

Abstract: Transdermal (TTS) fentanyl therapy has emerged as an effective alternative to the use of oral opioids for the control of pain in certain cancer patients. These patients are those with moderate to severe chronic pain, with a stable baseline pain pattern. Patients receiving this treatment should first be titrated to stable pain relief with oral opioids and should have recourse during therapy to fast-acting, short-duration analgesics for the control of incident pain. TTS fentanyl dosing schedules should be based upon the patient's requirement for rescue dosing and duration of effective pain control. The average requirement to change fentanyl patches is every 72 h, although 48-h dosing is necessary in a few patients. This novel route of fentanyl administration allows convenient outpatient treatment, the possibility of a lower incidence of side effects, and may thus aid compliance.

Vitamin D analogs: new therapeutic agents for the treatment of squamous cancer and its associated hypercalcemia.

Abstract: We have examined the in vitro effects of 1,25 dihydroxy-vitamin D3 [1,25(OH)2D3] and of two side-chain modified analogs of 1,25(OH)2D3 (EB1089 and MC903) on cell growth and parathyroid hormone related peptide (PTHRP) production in immortalized (HPK1A) and neoplastic (HPK1A-ras) keratinocytes. Cell proliferation was strongly inhibited by 1,25(OH)2D3 and its analogs in HPK1A cells, and in this system EB1089 was 10-100 times more potent than 1,25(OH)2D3 or MC903. A similar effect on cell proliferation was observed in HPK1A-ras cells; however, 10-fold higher concentrations of 1,25(OH)2D3 or its analogs were required. We also observed a strong and dose-dependent inhibitory effect of these compounds on PTHRP secretion and gene expression. In both immortalized and neoplastic keratinocytes, EB1089 was 10-100 times more potent than 1,25(OH)2D3 or MC903 on inhibiting PTHRP production. However, although effective in HPK1A-ras cells, 10-fold higher concentrations of 1,25(OH)2D3 or its analogs were required to produce similar actions in this neoplastic model. These studies therefore demonstrate that a 1,25(OH)2D3 analog with low calcemic potency in vivo (EB1089) can inhibit keratinocyte proliferation and PTHRP production by such cells with greater potency than 1,25(OH)2D3. The observed effects of such analogs in neoplastic keratinocytes predicts their potential usefulness in vivo in inhibiting squamous cancer growth and its associated hypercalcemia.

Is Navoban® (tropisetron) as effective as Zofran® (ondansetron) in cisplatin-induced emesis?

Abstract: The purpose of this study was to evaluate and compare the antiemetic effectiveness and tolerability of Navoban® (tropisetron) and Zofran® (ondansetron) following high-dose (≥ 50 mg/m2) cisplatin chemotherapy. In a randomised, multi-centre, double-blind, double-dummy, parallel group study, 117 evalua

Reversal of multiple drug resistance in vitro by phosphorathioate oligonucleotides and ribozymes

Abstract: In the present study we investigated the effectiveness of 14, 15 and 18 nucleotide antisense phosphorothioate oligonucleotides (S-ODNs) directed to four different regions of the published mdr-1 gene sequence to reduce the level of mdr-1 gene product (p170, P-glycoprotein) and its function in the over-expressing cell lines Lo-VoDxR, S180DxR and KBChR8-5. The highest efficiency in reduction of multiple drug resistance was obtained at a concentration of 2 microM. In proliferation assays a growth reduction of 50% was observed after exposure of doxorubicin-resistant cells to S-ODN3. p170 protein expression of the resistant cell line LoVoDxR was reduced to the level of the sensitive cell line LoVo as shown by Western blot analysis. S-ODN3 reduced the ID50 of the two human cell lines up to 60% (LoVoDxR) and 21% (KBChR8-5), respectively, but showed no effect in the murine cell line S180DxR. In contrast, S-ODN1 was most effective in the murine system (67% reduction of the ID50), less effective in LoVoDxR (34%) and exhibited no effect in cell line KBChR8-5. Based on the results with the antisense oligonucleotides, a ribozyme directed against the mRNA target region of S-ODN3 was designed. This ribozyme was able to reduce the mdr-1 mRNA in total RNA preparations from cell line LoVoDxR up to 80% after an incubation time of 6 h in the presence of 10 mM MgCl2 at pH 7.5. A modified ribozyme was investigated in cell culture and reduced chemo-resistance of the resistant cell line LoVoDxR and ex vivo cultured blasts of acute myeloid leukemia patients up to 50%.

Comparison of sulforhodamine B, tetrazolium and clonogenic assays for in vitro radiosensitivity testing in human ovarian cell lines.

Abstract: The radiation sensitivity of six human ovarian tumor cell lines was evaluated using sulforhodamine B (SRB), tetrazolium (MTT) and clonogenic assays. Radiobiological parameters calculated from a linear quadratic model (SF2, alpha, beta) as well as from a single-hit multitarget model (D(o), Dq, n) and from the area under the dose-response curve (mean inactivation dose; MID) were compared. If the values deduced from MTT experiments were statistically comparable to those obtained from clonogenic assays, significant differences were observed between SRB and the two other assays that concerned the results achieved with the highest radiation doses tested (6-8 Gy), yielding a surviving fraction of approximately 20%. In addition, the intra- and inter-experimental variation of SRB dramatically increased within this range of radiation doses. However, up to 6 Gy, the SRB assay proved to be statistically comparable to MTT and clonogenic assays, and allowed the calculation of SF2, alpha and MID radiobiological parameters.

Transdermal fentanyl: a new step on the therapeutic ladder.

Abstract: The high efficacy, low molecular weight and high lipid solubility of fentanyl make it a suitable agent for transdermal administration. Effective plasma concentrations are maintained for up to 48-72 hours after application of a transdermal therapeutic system (TTS) fentanyl patch. In a multicentre study, slow-release morphine was replaced by TTS fentanyl according to a special calculation table (10 mg oral morphine corresponding to approximately 0.1 mg TTS fentanyl). Ninety-eight patients were included in the study. Due to protocol infringements, however, the switch from oral morphine to TTS fentanyl could be assessed for only 38 patients. The changeover at a ratio of 100:1 proved to be safe and effective and a good alternative therapy to conventional strong opioids. The majority of the patients wished to continue TTS fentanyl therapy at the end of the study period. Side effects were similar to those associated with other opioids. However, TTS fentanyl was associated with a distinct decrease in constipation and a significant reduction in the use of laxatives. Furthermore, there were some indications that compliance may be increased with TTS fentanyl. Special indications for chronic pain therapy using transdermal opioids include head and neck and gastro-intestinal tract cancer. In these cases, TTS fentanyl may be the final non-invasive form of analgesic therapy which allows the patient to maintain a normal lifestyle. TTS fentanyl thus represents a new alternative for therapy with strong opioids on step III of the World Health Organization analgesic ladder.

The pattern of emesis following high-dose cyclophosphamide and the anti-emetic efficacy of ondansetron.

Abstract: Two randomized, double-blind placebo-controlled ondansetron dose ranging studies in patients receiving high-dose cyclophosphamide (with or without doxorubicin) were completed in the US. These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has a long latency of onset (8-13 h) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors.

Development of drug resistance is reduced with idarubicin relative to other anthracyclines.

Abstract: Multidrug resistance (MDR) is associated with poor prognosis in leukemia, and anthracyclines, which are used in the treatment of leukemia, are associated with the expression of P-glycoprotein and the development of MDR. We report here that idarubicin, a new anthracycline approved for use in the treatment of acute myelogenous leukemia (AML), did not induce P-glycoprotein expression in the K562 human leukemia cell line under conditions where daunorubicin, doxorubicin and epirubicin did induce expression of P-glycoprotein. The P-glycoprotein expressing, multidrug resistant sublines developed to daunorubicin (K/DNR), doxorubicin (K/DOX) and epirubicin (K/EPR) were cross-resistant to the other anthracyclines and to vinblastine, taxol, colchicine and actinomycin D, but were not resistant to idarubicin or etoposide. The idarubicin treated subline, K/IDA, was only resistant to taxol but was 12-fold sensitized to etoposide, suggesting that idarubicin had affected topoisomerase II in this subline.

Platin salts-induced hemolytic anemia: cisplatin- and the first case of carboplatin-induced hemolysis.

Abstract: Anemia is a common side effect of cisplatin, especially after repeated infusions. The primary mechanisms is a myelosuppression caused by cisplatin's interference with iron metabolism, resulting in a lower count of red cell precursors. Some authors report a hemolytic anemia similar to penicillin-induced anemia, in which hemolysis is caused by an antiglobulin antibody directed against red cell membrane-bound cisplatin. The authors report two cases of cisplatin-induced anemia and suggest that the immune-complex hypothesis is responsible for hemolysis. The first case of carboplatin-induced hemolysis is also reported. Mechanisms of hemolysis and clinical practice are discussed.