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PubMedDate not supplied

A novel approach for improving the efficacy of experimental cancer chemotherapy using combinations of anticancer drugs and L-histidinol.

One of the major limitations to the chemical management of human malignancies is the failure of most antineoplastic agents to act specifically against tumour cells. A novel approach for improving both the specificity and the efficacy of experimental cancer chemotherapy is described in this review. The approach is based upon the use of L-histidinol in combination with conventional anticancer drugs. L-Histidinol, a structural analogue of the essential amino acid L-histidine, is a reversible inhibitor of protein biosynthesis which evokes disparate responses from non-tumorigenic and tumorigenic cells in culture. Whereas L-histidinol protects a wide variety of phenotypically normal cells from anticancer drug toxicity, it enhances the vulnerability of tumorigenic cells to the same agents. More importantly, these remarkable properties of L-histidinol are retained in tumour-bearing animals. Thus, L-histidinol diminishes the myelocytoxicity otherwise associated with the in vivo use of agents such as cytosine arabinoside and 5-fluorouracil. Simultaneously, L-histidinol increases the inherent capacities of these two antimetabolites to eradicate in situ tumour cells. More recently, it has been found that L-histidinol can increase both the specificity and the efficacy of a number of other antineoplastic agents. For example, alkylating agents such as BCNU, cyclophosphamide and cis-platinum, as well as the antitumour antibiotic daunomycin, can be combined with L-histidinol to provide curative treatment for tumour-bearing animals under conditions where these drugs, on their own, have little or no impact on survival. These results demonstrate that the L-histidinol/anticancer drug combination approach to chemotherapy is effective with a variety of clinically-relevant antineoplastic agents. However, it remains to be demonstrated whether this approach will prove applicable in, or effective for, human cancer chemotherapy.

Animals↗

PubMed1988

Longitudinal analysis of psychological adaptation among family members of patients with cancer.

A growing body of research suggests that a cancer diagnosis reverberates throughout the family system. The majority of studies provide evidence of the psychological distress experienced by family members at the time of diagnosis and during terminal and early bereavement stages. Increasingly, however, patients survive a cancer diagnosis. Therefore, their experience and that of family members more closely approximates living with a chronic illness. In this longitudinal study of 143 pairs of patients and significant others it was found that a substantial minority of significant others experienced psychological distress up to one year after the patient's initial diagnosis. The psychologically vulnerable group of significant others included an initially poor functioning group who remained so over time as well as a group whose mental health status declined over time. Personal and social resources were more important factors in declining mental health than illness-related factors.

Adaptation, Psychological↗

PubMed2003

Delivery of preventive services for low-income persons over age 50: a comparison of community health clinics to private doctors' offices.

This study focused on the use of 14 evidence-based preventive services for the low-income population over age 50: colorectal, breast and cervical cancer screening, cholesterol screening, counseling around diet, exercise, tobacco, alcohol and illicit drugs, and immunizations for influenza, tetanus and pneumonia. Population characteristics and rates of delivery of these preventive services are compared for low-income users of community health clinics vs private doctors' offices/HMOs. Three nationally representative data-files from the National Health Interview Survey--the Person-Level File, Sample Adult File, and Sample Adult Prevention File--were linked to obtain the necessary data on preventive services use in the 12,024 persons over age 50. Among the population of persons over age 50 living below 200% of the poverty threshold, those using community clinics were more likely to be younger, a racial or ethnic minority, less formally educated, in poorer health, uninsured, and more likely to face time, transportation or cost barriers to obtaining health care (p < .01 for all comparisons), than their counterparts using private doctors' offices/HMOs. Community health clinics performed as well as private doctors/HMOs in the delivery of cancer screening, cholesterol screening and immunizations to lower income persons over 50 years. Rates of counseling about diet and exercise were higher among users of private doctor's offices than among users of community health clinics users (40% vs. 31% respectively, p = .02). Despite the severe resource constraints under which they operate, and the greater vulnerability of the population they serve, community clinics deliver preventive services at rates comparable to private doctors' offices and HMOs.

Community Health Centers↗

PubMed1985

Prognostic risk assessment in primary breast cancer by behavioral and immunological parameters.

Although findings from recent animal studies suggest that behavioral factors such as "helplessness" play a role in cancer progression, very few such studies with humans have been carried out. The study investigated the predictive power of an immunologic effector cell, the natural killer (NK) cell, as well as selected psychological and demographic factors, to breast cancer prognostic risk status. It was found that NK activity predicted the status of cancer spread to the axillary lymph nodes. Patients who had low levels of NK activity were rated as well-adjusted to their illness; patients who had higher NK activity appeared to be distressed or maladjusted. These findings are discussed in the light of recent animal findings linking environmental stress and behavioral responsiveness to biological vulnerability via endocrine and immune pathways.

Adult↗

PubMed1994

The new combined surgical approach for cancer involving the base of tongue-supraglottic complex.

The base of the tongue, valleculae, preepiglottic space, and supraglottic area of the larynx develop from an unpaired central area, i.e., "hypobranchial eminance," unlike oral tongue and vocal cords, which are independently unilateral and paired in character. These areas should be known as "base of tongue-supraglottic complex." Lymphatic criss-cross is common in this area. This paper delineates the usefulness of the combined surgical procedure. The extensive cancer in the base of tongue-supraglottic complex has represented a challenge to the head and neck surgeon. A combined procedure, i.e., supraglottic laryngectomy with a deep and extensive sagittal surgical incision made directly through the lip-mandible-oral tongue, provides wider exposure without severing any major nerves or blood vessels, and the vulnerable bilateral lymph bearing area of the neck can be addressed adequately for elective or curative neck dissection. Preoperative dental assessment, visual and palpatory assessment of tumor extent under anesthesia (EUA) helps in careful patient selection. Rehabilitation is expected to take longer, but not hospitalization, which is understood in surgical resections of this magnitude. The Tata Memorial Hospital experience with this new surgical approach is described in detail.

Carcinoma, Squamous Cell↗

PubMed1999

[Smoking and pregnancy].

Smoking is disadvantageous for health in every respect. This is a fortiori the case during pregnancy. Pregnant women who smoke burden their unborn child with a mixture of hundreds of tobacco combustion products, dozens of which have been proved to be harmful, apart from the negative influence of the smoke induced blockade of the haemoglobin by carbon monoxide. Since the embryonic and foetal tissues which are formed in a short period, are particularly vulnerable, many detrimental effects can be observed. The fertility rate of women who smoke is reduced and their risk of abortion, miscarriage and preterm delivery is increased. Babies born to women who smoked during pregnancy have lower birth weights and are less developed. They run an increased risk of many disorders including asthma and even cancer. Their cancer risk seems even to be increased in adulthood. Smoking fathers also damage the development of their unborn child.

Adult↗

PubMed1994

[The age for beginning and the frequency for performing the Pap test].

The increase in sexual activity among teenagers has been well documented. One apparent result is the increasing prevalence of cervical cytological abnormalities in this age group over the last 20 years. The adolescent cervix appears to be especially vulnerable to the initiation of carcinogenesis. Consequently, the significance of early age at first coitus is thought to be related to the biologic changes that occur in the cervix during puberty. Large epidemiologic studies have implicated sexuality as the initiator of a sequence of multistage events that destabilize the healthy cervix and culminate in cervical cancer. The median interval between age at first coitus and the development of CIN1 is 9 years, with a progressive 2.5 year increase for each degree of progression from CIN 1 through 3. Unfortunately, the precise mechanism by which that biologic variable, early age at first coitus, predisposes to CIN remains enigmatic. Nevertheless, there is no doubt that the earlier the age at first coitus, the higher the risk factor. Among virgins the incidence of cervical cancer is essentially zero. Among sexually active adolescent girl no cases of invasive carcinoma have been found, but carcinoma in situ had a prevalence rate of 2.6 per 1,000 15-19 years old, whereas cervical dysplasia ranges from 0.8 to 3.5% of screened sexually active teenagers populations. Adolescents who have never been sexually active clearly do not need to be screened for cervical cancer. On the contrary teenagers with the risk factors of sexually transmitted disease or multiple sex partners should be annually screened soon after onset of sexual activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1996

Primary care of lesbian and gay patients: educating ourselves and our students.

Although a significant proportion of the population is gay or lesbian, physicians receive little formal training about homosexuality, and the unique health care needs of these patients are often ignored. Gay men and women may have higher rates of depression, suicide, alcoholism, certain cancers, and cardiovascular disease than their heterosexual counterparts. In addition, they are at risk of being victims of violence because of their sexual orientation. Due to fear of stigmatization by the medical community, the most significant health risk for lesbians, gays, and bisexuals may be that they avoid routine health care. Gay youth are particularly vulnerable to internal and external pressures, resulting in higher rates of substance abuse, suicide, and homelessness. Older gay men and women, who generally view themselves positively, may be troubled by declining health and loneliness. Physicians can improve the health care of gay and bisexual men and women and their families by maintaining a non-homophobic attitude toward these patients, distinguishing sexual behavior from sexual identity, communicating with gender-neutral terms, and maintaining awareness of how their own attitudes affect clinical judgment. Medical educators should avoid making assumptions about the sexuality of their residents and students. Institutions need to realize that the presence of supportive heterosexual and openly gay faculty will help create an environment that fosters learning for all students. Scant research exists about the best ways to teach about the special challenges gay men and lesbians face. However, the majority of surveyed medical students prefer that issues regarding gays and lesbians be integrated throughout the entire medical school curriculum.

Adolescent↗

PubMed1998

A clinician's guide to a woman's heart.

Contrary to the perception of most women that breast cancer is the leading cause of death in women, it is heart disease and stroke that claim the most lives of women older than 35 years in the United States. The prevalence of cardiovascular disease is likely to increase as more women--notably the "baby boomers"--enter the menopausal period, a time of increased cardiac vulnerability. Primary care physicians should be on the forefront in taking an inventory of risk factors in their female patients and in educating them about the reality of heart disease in their gender and about the risk factors that these patients can modify to decrease their risk. To aid in their efforts, this article provides an overview of those risk factors that are modifiable, such as weight reduction, exercise, and smoking cessation. It also offers an evaluation of the benefit and nonbenefit of vitamin and herbal supplements in reduction of cardiac events.

Adult↗

PubMed1996

Selection for beta 2-microglobulin mutation in mismatch repair-defective colorectal carcinomas.

Novel peptide antigens complexed with human leukocyte antigen (HLA) and beta 2-microglobulin (beta 2M) molecules are presented at the cell surface to cytotoxic T lymphocytes (CTLs), provoking lysis of the antigen-presenting cell [1]. In tumor cells, genetically altered or abnormally expressed proteins provide a source of peptides that can be presented to CTLs; the resulting anti-tumour CTL responses may provide part of the body's defence against cancer. Disabling mutations in the HLA and beta 2M proteins required for peptide presentation allow a tumour cell to escape destruction by CTLs. Cells with deficient DNA mismatch repair have high spontaneous mutation rates [2] and produce many altered proteins that are a potential source of numerous unique peptides. Mutator tumour cells might therefore be particularly vulnerable to immune surveillance and CTL attack. Mutator phenotypes [3,4] and loss of beta 2M (or HLA) expression [5,6] are both relatively common among sporadic colorectal tumours. We have compared the frequency of beta 2M mutations in sporadic colorectal and other tumours with and without a mutator phenotype. Mutations were more frequent among colorectal tumours with the microsatellite instability indicative of a defect in DNA mismatch repair. The inactivating beta 2M mutations were predominantly frameshifts, which is consistent with the underlying mismatch repair defects. Evasion of immune surveillance by acquiring beta 2M mutations therefore occurs at high frequency in tumour cells with a mutator phenotype due to defective DNA mismatch repair.

Colorectal Neoplasms↗

PubMed1987

Cisplatin nephrotoxicity: insights into mechanism.

Cis-dichlorodiammine platinum (II), or cisplatin, is currently among the most widely used agents in the chemotherapy of cancer. The chief limit to its greater efficacy is its nephrotoxicity. Acute and chronic nephrotoxicity of cisplatin occurs in man and animals especially after repeated administration. Morphological damage is restricted to the P3 segment of the proximal tubule. Abnormalities of water and solute reclamation and transglomerular passage of fluid are commonly associated with cisplatin nephrotoxicity. The vulnerability of the kidney to cisplatin may be related to its function as the primary excretory organ for platinum. Platinum binds to multiple cellular organelles and macromolecules, yet the precise mechanism of its cytotoxicity has not been delineated. Because abnormalities in renal function are preceded by a period where gross renal function appears normal, it is an ideal model to study the early physiological and biochemical determinants of metal induced acute renal failure.

Acute Kidney Injury↗

PubMedDate not supplied

The catalytic subunit of telomerase is expressed in developing brain neurons and serves a cell survival-promoting function.

Telomerase, a specialized reverse transcriptase (RT) linked to cell immortalization and cancer, has been thought not to be expressed in postmitotic cells. We now report that telomerase activity and its essential catalytic subunit, telomerase reverse transcriptase (TERT), are expressed in neurons in the brains of rodents during embryonic and early postnatal development, and are subsequently downregulated. Suppression of TERT expression in cultured embryonic hippocampal neurons increases their vulnerability to apoptosis and excitotoxicity. Overexpression of TERT in PC12 cells suppresses apoptosis induced by trophic factor withdrawal. TERT exerts its anti-apoptotic action at an early stage of the cell death process prior to mitochondrial dysfunction and caspase activation. TERT may serve a neuron survival-promoting function in the developing brain, and downregulation of TERT in the adult brain may contribute to increased neuronal vulnerability in various age-related neurodegenerative disorders.

Aging↗

PubMed1978

Predictive experimental animal tumor models: a concept.

As an introduction to the session on Animal Tumor Models, a concept of animal model systems in presented that differentiates between models of organ-related diseases such as prostate or bladder cancer and models of a certain class of neoplasms found within a specific organ disease. Thus defined, no one animal tumor can completely represent and be predictive for a disease entity, no more so than can a single clinical experience with prostate cancer, e.g., be representative of all clinical cases. Rather, a block of animal tumors originating from a specific organ that reflects a spectrum of carefully defined growth patterns and reactivities best mimics the overall responses obtained clinically. Because immunotherapy is most logically visualized and applied in an adjuvant mode, its effectiveness as a therapeutic modality is vulnerable to the vagaries of individual tumor response to a primary modality. Therefore, the selection of appropriate tumor models for developmental studies in immunotherapy is critical, and the need for well-defined and characterized test systems in terms of chemotherapy and radiation responsiveness is emphasized.

Animals↗

PubMed2026

CRISPR/Cas9 screening revealed BIRC6-AS1/BIRC6 mediates abiraterone resistance via NHEJ pathway-dependent A20 degradation in prostate cancer.

Abiraterone acetate is a standard-of-care therapy for prostate cancer (PCa). However, resistance frequently emerges, often characterized by the progression to AR-independent phenotypes. Employing a genome-wide CRISPR/Cas9 library screening strategy, we identified 523 long non-coding RNAs (lncRNAs) and 2,183 protein-coding genes as potential candidates associated with abiraterone resistance. Notably, a pair of sense-antisense genes, BIRC6-AS1/BIRC6, was identified as a significant contributor to abiraterone resistance, serving as a critical survival factor in AR-independent contexts. BIRC6-AS1 depletion led to a reduction in both the mRNA and protein levels of BIRC6. Moreover, depletion of either BIRC6-AS1 or BIRC6 enhanced the sensitivity of PCa cells to abiraterone in both in vitro and in vivo settings. Further investigation revealed that BIRC6-AS1 stabilized the mRNA of BIRC6 through interaction with ILF2. Suppression of either BIRC6-AS1 or BIRC6 attenuated non-homologous end joining (NHEJ) repair activity, resulting in the disassembly of 53BP1 foci at DNA damage sites and an increased accumulation of DNA damage, thereby exposing a vulnerability in AR-independent resistant cells. Mechanistically, BIRC6 interacted with A20 and facilitated the K48-linked ubiquitination and subsequent degradation of A20 at the K337 residue. Additionally, A20 knockdown effectively reversed the abiraterone sensitivity induced by BIRC6-AS1 depletion. Collectively, our study provides a landscape of lncRNAs and protein-coding genes associated with abiraterone resistance and suggests that targeting the BIRC6-AS1/BIRC6 axis represents a potential therapeutic strategy to eradicate AR-independent resistant tumors in prostate cancer.

Journal Article↗

PubMed2004

Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors.

BACKGROUND: As the number of long-term survivors of childhood cancer has grown, it has become increasingly clear that central nervous system therapy may have serious long-term effects on cognition and endocrine function. These complications have been studied most extensively in children with brain tumors and leukemia. REVIEW SUMMARY: Children with acute lymphoblastic leukemia previously treated with cranial irradiation are at risk for cognitive decline. Chemotherapy-only regimens, which rely on high-dose frequently administered methotrexate, are also associated with producing cognitive dysfunction. Children irradiated for brain tumors are even more vulnerable. Risk factors include perioperative morbidity, young age, large-volume high-dose cranial irradiation, supra-tentorial location of tumor, moyamoya syndrome, and leukoencephalopathy. Cognitive decline is progressive over at least a decade. The most common radiation-induced endocrinopathies are hypothyroidism and growth hormone deficiency. Treatment effects on growth are multifactorial and include growth hormone deficiency,spinal shortening, precocious puberty, undetected hypothyroidism,and poor nutrition. Fifty percent to 80% of children treated with craniospinal radiation for brain tumors will experience growth failure. In hopes of reducing neurotoxicity, current treatments limit the dose and volume of radiation while adding chemotherapy. Results have not been uniformly positive, however, and may increase toxicity in some cases. CONCLUSIONS: The standard of care in 2004 is that children who have been treated for brain tumors and leukemia should be monitored for cognitive and endocrine dysfunction. Until effective non-neurotoxic treatment is identified, long-term effects assessments are essential to maximize the quality of life of survivors of childhood cancer.

Brain Neoplasms↗

PubMed1984

Responsiveness of testis morphology to chemotherapy in childhood leukemia.

The appearance of seminiferous tubules and interstitial cells of children, aged 2.5 to 13 years, affected by acute lymphoblastic leukemia was analyzed in sections. The testicular biopsies were performed at the end of therapy (vincristine, prednisone, L-asparaginase, 6-mercaptopurine, intrathecal methotrexate), which was affected for the same period and at the same doses. Three age groups were considered (I, 2.5 to 5 years; II, 6 to 9 years; III, 12 to 13 years). Age groups I and II presented damage of some tubules (25-35%) and areas of degeneration. Histometric analysis performed for A type spermatogonial population gave a mean value corresponding to controls in age group I and a mean value significantly lower with respect to controls in age group II. Moreover, age group II presented a lack of increase in tubular cross section. These results suggest that there is a vulnerability both of whole tubules and of some areas of Sertoli cells and germ cels to cytotoxic-induced damage. Leydig cells appear to be the cells least sensitive to drugs, and hormonal data indicate that the hypothalamic pituitary function appears to be intact, despite chemotherapy. Long-term prospective studies of reproductive function in children receiving cancer chemotherapy are needed to determine the magnitude and duration of damage resulting from therapeutic treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Relocation stress syndrome: the case of palliative care patients.

Transfer of patients from palliative care services to nursing homes is necessary at present when a patient is relatively stable, but does not have adequate support systems at home. With the ageing of the population and the increasing incidence of cancer, the need for inpatient palliative care beds is growing with corresponding pressure for patients to be transferred to nursing homes. Transfer to a nursing home in the general population has been described extensively in the gerontology literature where a critical early phase of relocation has been identified by a high incidence of morbidity and mortality. The vulnerability of terminally ill patients means that they are at increased risk of suffering from stress associated with a transfer. The prognosis of a patient may be shorter than the time required for adjustment to the patient's new home. The issues surrounding transfer of palliative care patients to nursing homes and possible strategies designed to reduce distress associated with transfers are explored.

Adaptation, Psychological↗

PubMed2004

Use of strong opioids for non-cancer pain in the community: a case study.

The continued extension of prescribing rights among nurses may necessitate that effective pain management will require more involvement of nurses in the prescription of controlled drugs. The prescription of strong opioid analgesic drugs for chronic non-cancer pain (CNCP) is viewed as controversial. Misconceptions about opioid drugs fuel this controversy. This case study highlights the knowledge gap that exists between pain and addiction medicine and highlights the problems that CNCP patients treated in the community with opioid therapy may encounter. Community nurses are in an ideal position to be instrumental in identifying such vulnerable patients and ensuring that appropriate interventions are available.

Analgesics, Opioid↗